Substituted imidazoquinolines, imidazopyridines, and imidazonaphthyridines

ABSTRACT

Imidazo-quinoline, -pyridine, and -naphthyridine ring systems (particularly quinolines, tetrahydroquinolines, pyridines, [1,5]naphthyridines, [1,5]tetrahydronaphthyridines) substituted at the 1-position with a cyclic substituent, pharmaceutical compositions containing the compounds, methods of making these compounds, and methods of use of these compounds as immunomodulators, for inducing cytokine biosynthesis in animals and in the treatment of diseases including viral and neoplastic diseases are disclosed.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.14/021,197, filed, Sep. 9, 2013, now U.S. Pat. No. 9,006,264, which is acontinuation of Ser. No. 12/974,459, filed Dec. 21, 2010, now U.S. Pat.No. 8,541,438, which is a divisional of U.S. patent application Ser. No.11/570,707, filed Dec. 15, 2006, now U.S. Pat. No. 7,884,207, which is aNational Stage Filing of International Application No.PCT/US2005/021445, filed Jun. 17, 2005, which claims priority to U.S.Provisional Application Ser. No. 60/581,274, filed Jun. 18, 2004, all ofwhich are incorporated herein by reference.

BACKGROUND

In the 1950's the 1H-imidazo[4,5-c]quinoline ring system was developedand 1-(6-methoxy-8-quinolinyl)-2-methyl-1H-imidazo[4,5-c]quinoline wassynthesized for possible use as an antimalarial agent. Subsequently,syntheses of various substituted 1H-imidazo[4,5-c]quinolines werereported. For example,1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinoline was synthesized as apossible anticonvulsant and cardiovascular agent. Also, several2-oxoimidazo[4,5-c]quinolines have been reported.

Certain 1H-imidazo[4,5-c]quinolin-4-amines and 1- and 2-substitutedderivatives thereof were later found to be useful as antiviral agents,bronchodilators and immunomodulators. Subsequently, certain substituted1H-imidazo[4,5-c]pyridin-4-amine, quinolin-4-amine,tetrahydroquinolin-4-amine, naphthyridin-4-amine, andtetrahydronaphthyridin-4-amine compounds as well as certain analogousthiazolo and oxazolo compounds were synthesized and found to be usefulas immune response modifiers, rendering them useful in the treatment ofa variety of disorders.

There continues to be interest in the imidazoquinoline ring system, aswell as other imidazo ring systems, and there is a continuing need forcompounds that have the ability to modulate the immune response, byinduction of cytokine biosynthesis or other mechanisms.

SUMMARY

The present invention provides a new class of compounds that are usefulin inducing cytokine biosynthesis in animals. Such compounds are of thefollowing Formula (I):

wherein R_(A), R_(B), R₂, R′, Z, and m are as defined below.

Compounds of Formula (I) include imidazo-quinoline, -pyridine, and-naphthyridine ring systems, particularly quinolines,tetrahydroquinolines, pyridines, 1,5-naphthyridines, and1,5-tetrahydronaphthyridines, substituted at the 1-position with acyclic substituent.

The compounds of Formula I are useful as immune response modifiers dueto their ability to induce cytokine biosynthesis (e.g., induces thesynthesis of at least one cytokine) and otherwise modulate the immuneresponse when administered to animals. This makes the compounds usefulin the treatment of a variety of conditions such as viral diseases andtumors that are responsive to such changes in the immune response.

The invention further provides pharmaceutical compositions containing aneffective amount of a compound of Formula I and methods of inducingcytokine biosynthesis in an animal, treating a viral infection and/ortreating a neoplastic disease in an animal by administering an effectiveamount of a compound of Formula I to the animal.

In addition, methods of synthesizing compounds of Formula I useful inthe synthesis of these compounds are provided.

As used herein, “a,” “an,” “the,” “at least one,” and “one or more” areused interchangeably.

The terms “comprises” and variations thereof do not have a limitingmeaning where these terms appear in the description and claims.

The above summary of the present invention is not intended to describeeach disclosed embodiment or every implementation of the presentinvention. The description that follows more particularly exemplifiesillustrative embodiments. In several places throughout the application,guidance is provided through lists of examples, which examples can beused in various combinations. In each instance, the recited list servesonly as a representative group and should not be interpreted as anexclusive list.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS OF THE INVENTION

The present invention provides compounds of the following Formula (I):

as well as more specific compounds of the following Formulas (II, III,IV, V, VI, VII, VIII, IX, and X):

as well as intermediates of the following Formulas (XI) and (XII):

and pharmaceutically acceptable salts thereof.

In one embodiment, there is provided a compound of the Formula (I):

wherein:

m is an integer from 1 to 5;

R′ is selected from the group consisting of:

-   -   hydroxy,    -   thiol,    -   —S(O)₀₋₂-alkyl,    -   —S(O)₂—NH—R₉,    -   alkoxy,    -   —O—C₁₋₃ alkylene-S(O)₂-alkyl,    -   —N(R₉)₂, and    -   —NH-Q-R₄;

Z is selected from the group consisting of:

-   -   a bond,    -   C₁₋₅ alkylene,

A′ is selected from the group consisting of:

-   -   —O—,    -   —C(O)—,    -   —N(R₈)—,    -   —N(Q-R₄)—,    -   —N(C₁₋₅ alkylene-NH-Q-R₄)—,    -   —N(C₁₋₅ alkylene-W—NH—R₈)—, and    -   —S(O)₀₋₂—;

R₂ is selected from the group consisting of:

-   -   —R₄,    -   —X—R₄,    -   —X—Y—R₄, and    -   —X—R₅;

R_(A) and R_(B) are each independently selected from the groupconsisting of:

-   -   hydrogen,    -   halogen,    -   alkyl,    -   alkenyl,    -   alkoxy,    -   alkylthio, and    -   —N(R₉)₂;

or when taken together, R_(A) and R_(B) form a fused aryl ring orheteroaryl ring containing one heteroatom selected from the groupconsisting of N and S wherein the aryl or heteroaryl ring isunsubstituted or substituted by one or more R groups;

or when taken together, R_(A) and R_(B) form a fused 5 to 7 memberedsaturated ring, optionally containing one heteroatom selected from thegroup consisting of N and S, and unsubstituted or substituted by one ormore R groups;

R is selected from the group consisting of:

-   -   halogen,    -   hydroxy,    -   alkyl,    -   alkenyl,    -   haloalkyl,    -   alkoxy,    -   alkylthio, and    -   —N(R₉)₂;

X is selected from the group consisting of alkylene, alkenylene,alkynylene, arylene, heteroarylene, and heterocyclylene wherein thealkylene, alkenylene, and alkynylene groups can be optionallyinterrupted or terminated with arylene, heteroarylene, orheterocyclylene, and optionally interrupted by one or more —O— groups;

Y is selected from the group consisting of:

-   -   —S(O)₀₋₂—,    -   —S(O)₂—N(R₈)—,    -   —C(R₆)—,    -   —C(R₆)—O—,    -   —O—C(R₆)—,    -   —O—C(O)—O—,    -   —N(R₈)-Q-,    -   —C(R₆)—N(R₈)—,    -   —O—C(R₆)—N(R₈)—,    -   —C(R₆)—N(OR₉)—,

R₄ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl, wherein the alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted orsubstituted by one or more substituents independently selected from thegroup consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy,halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy,arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy,heterocyclyl, amino, acetylamino, alkylamino, dialkylamino,(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl,and heterocyclyl, oxo;

R₅ is selected from the group consisting of:

R₆ is selected from the group consisting of ═O and ═S;

R₇ is C₂₋₇ alkylene;

R₈ is selected from the group consisting of hydrogen, alkyl,alkoxyalkylenyl, and arylalkylenyl;

R₉ is selected from the group consisting of hydrogen and alkyl;

R₁₀ is C₃₋₈ alkylene;

R₁₁ is selected from the group consisting of hydrogen, alkyl, halogen,and trifluoromethyl;

R₁₂ is selected from the group consisting of hydrogen, alkyl, phenyl,2-pyridyl, 3-pyridyl, and 4-pyridyl;

A is selected from the group consisting of —O—, —C(O)—, —S(O)₀₋₂—,—CH₂—, and —N(R₄)—;

Q is selected from the group consisting of a bond, —C(R₆)—,—C(R₆)—C(R₆), —S(O)₂—, —C(R₆)—N(R₈)—W—, —S(O)₂—N(R₈)—, —C(R₆)—O—, and—C(R₆)—N(OR₉)—;

V is selected from the group consisting of —C(R₆)—, —O—C(R₆)—,—N(R₈)—C(R₆)—, and —S(O)₂—;

W is selected from the group consisting of a bond, —C(O)—, and —S(O)₂—;and

a and b are independently integers from 1 to 6 with the proviso that a+bis ≦7;

with the proviso that when Z is a bond or C₁₋₅ alkylene then R′ is otherthan —O—C₁₋₃ alkylene-S(O)₂-alkyl, and with the further proviso thatwhen Z is a bond or C₁₋₅ alkylene and R₂ is —X—Y—R₄ and Y is —N(R₈)-Q-,then Q is other than —C(R₆)—N(R₈)—W—;

or a pharmaceutically acceptable salt thereof.

In another embodiment, there is provided a compound of the Formula (II):

wherein:

m is an integer from 1 to 5;

n is an integer from 0 to 4;

R′ is selected from the group consisting of:

-   -   hydroxy,    -   thiol,    -   —S(O)₀₋₂-alkyl,    -   —S(O)₂—NH—R₉,    -   alkoxy,    -   —O—C₁₋₃ alkylene-S(O)₂-alkyl,    -   —N(R₉)₂, and    -   —NH-Q-R₄;

Z is selected from the group consisting of:

-   -   a bond,    -   C₁₋₅ alkylene,

A′ is selected from the group consisting of:

-   -   —O—,    -   —C(O)—,    -   —N(R₈)—,    -   —N(Q-R₄)—,    -   —N(C₁₋₅ alkylene-NH-Q-R₄)—,    -   —N(C₁₋₅ alkylene-W—NH—R₈)—, and    -   —S(O)₀₋₂—;

R₂ is selected from the group consisting of:

-   -   —R₄,    -   —X—R₄,    -   —X—Y—R₄, and    -   —X—R₅;

R is selected from the group consisting of:

-   -   halogen,    -   hydroxy,    -   alkyl,    -   alkenyl,    -   haloalkyl,    -   alkoxy,    -   alkylthio, and    -   —N(R₉)₂;

X is selected from the group consisting of alkylene, alkenylene,alkynylene, arylene, heteroarylene, and heterocyclylene wherein thealkylene, alkenylene, and alkynylene groups can be optionallyinterrupted or terminated with arylene, heteroarylene, orheterocyclylene, and optionally interrupted by one or more —O— groups;

Y is selected from the group consisting of:

-   -   —S(O)₀₋₂—,    -   —S(O)₂—N(R₈)—,    -   —C(R₆)—,    -   —C(R₆)—O—,    -   —O—C(R₆)—,    -   —O—C(O)—O—,    -   —N(R₈)-Q-,    -   —C(R₆)—N(R₈)—,    -   —O—C(R₆)—N(R₈)—,    -   —C(R₆)—N(OR₉)—,

R₄ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl, wherein the alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted orsubstituted by one or more substituents independently selected from thegroup consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy,halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy,arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy,heterocyclyl, amino, acetylamino, alkylamino, dialkylamino,(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl,and heterocyclyl, oxo;

R₅ is selected from the group consisting of:

R₆ is selected from the group consisting of ═O and ═S;

R₇ is C₂₋₇ alkylene;

R₈ is selected from the group consisting of hydrogen, alkyl,alkoxyalkylenyl, and arylalkylenyl;

R₉ is selected from the group consisting of hydrogen and alkyl;

R₁₀ is C₃₋₈ alkylene;

R₁₁ is selected from the group consisting of hydrogen, alkyl, halogen,and trifluoromethyl;

R₁₂ is selected from the group consisting of hydrogen, alkyl, phenyl,2-pyridyl, 3-pyridyl, and 4-pyridyl;

A is selected from the group consisting of —O—, —C(O)—, —S(O)₀₋₂—,—CH₂—, and —N(R₄)—;

Q is selected from the group consisting of a bond, —C(R₆)—,—C(R₆)—C(R₆), —S(O)₂—, —C(R₆)—N(R₈)—W—, —S(O)₂—N(R₈)—, —C(R₆)—O—, and—C(R₆)—N(OR₉)—;

V is selected from the group consisting of —C(R₆)—, —O—C(R₆)—,—N(R₈)—C(R₆)—, and —S(O)₂—;

W is selected from the group consisting of a bond, —C(O)—, and —S(O)₂—;and

a and b are independently integers from 1 to 6 with the proviso that a+bis ≦7;

with the proviso that when Z is a bond or C₁₋₅ alkylene then R′ is otherthan —O—C₁₋₃ alkylene-S(O)₂-alkyl, and with the further proviso thatwhen Z is a bond or C₁₋₅ alkylene and R₂ is —X—Y—R₄ and Y is —N(R₈)-Q-,then Q is other than —C(R₆)—N(R₈)—W—;

or a pharmaceutically acceptable salt thereof.

In another embodiment, there is provided a compound of the Formula(III):

wherein:

m is an integer from 1 to 5;

n is an integer from 0 to 4;

R′ is selected from the group consisting of:

-   -   hydroxy,    -   thiol,    -   —S(O)₀₋₂-alkyl,    -   —S(O)₂—NH—R₉,    -   alkoxy,    -   —O—C₁₋₃ alkylene-S(O)₂-alkyl,    -   —N(R₉)₂, and    -   —NH-Q-R₄;

Z is selected from the group consisting of:

-   -   a bond,    -   C₁₋₅ alkylene,

A′ is selected from the group consisting of:

-   -   —O—,    -   —C(O)—,    -   —N(R₈)—,    -   —N(Q-R₄)—,    -   —N(C₁₋₅ alkylene-NH-Q-R₄)—,    -   —N(C₁₋₅ alkylene-W—NH—R₈)—, and    -   —S(O)₀₋₂—;

R₂ is selected from the group consisting of:

-   -   —R₄,    -   —X—R₄,    -   —X—Y—R₄, and    -   —X—R₅;

R is selected from the group consisting of:

-   -   halogen,    -   hydroxy,    -   alkyl,    -   alkenyl,    -   haloalkyl,    -   alkoxy,    -   alkylthio, and    -   —N(R₉)₂;

X is selected from the group consisting of alkylene, alkenylene,alkynylene, arylene, heteroarylene, and heterocyclylene wherein thealkylene, alkenylene, and alkynylene groups can be optionallyinterrupted or terminated with arylene, heteroarylene, orheterocyclylene, and optionally interrupted by one or more —O— groups;

Y is selected from the group consisting of:

-   -   —S(O)₀₋₂—,    -   —S(O)₂—N(R₈)—,    -   —C(R₆)—,    -   —C(R₆)—O—,    -   —O—C(R₆)—,    -   —O—C(O)—O—,    -   —N(R₈)-Q-,    -   —C(R₆)—N(R₈)—,    -   —O—C(R₆)—N(R₈)—,    -   —C(R₆)—N(OR₉)—,

R₄ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl, wherein the alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted orsubstituted by one or more substituents independently selected from thegroup consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy,halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy,arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy,heterocyclyl, amino, acetylamino, alkylamino, dialkylamino,(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl,and heterocyclyl, oxo;

R₅ is selected from the group consisting of:

R₆ is selected from the group consisting of ═O and ═S;

R₇ is C₂₋₇ alkylene;

R₈ is selected from the group consisting of hydrogen, alkyl,alkoxyalkylenyl, and arylalkylenyl;

R₉ is selected from the group consisting of hydrogen and alkyl;

R₁₀ is C₃₋₈ alkylene;

R₁₁ is selected from the group consisting of hydrogen, alkyl, halogen,and trifluoromethyl;

R₁₂ is selected from the group consisting of hydrogen, alkyl, phenyl,2-pyridyl, 3-pyridyl, and 4-pyridyl;

A is selected from the group consisting of —O—, —C(O)—, —S(O)₀₋₂—,—CH₂—, and —N(R₄)—;

Q is selected from the group consisting of a bond, —C(R₆)—,—C(R₆)—C(R₆), —S(O)₂—, —C(R₆)—N(R₈)—W—, —S(O)₂—N(R₈)—, —C(R₆)—O—, and—C(R₆)—N(OR₉)—;

V is selected from the group consisting of —C(R₆)—, —O—C(R₆)—,—N(R₈)—C(R₆)—, and —S(O)₂—;

W is selected from the group consisting of a bond, —C(O)—, and —S(O)₂—;and

a and b are independently integers from 1 to 6 with the proviso that a+bis ≦7;

with the proviso that when Z is a bond or C₁₋₅ alkylene then R′ is otherthan —O—C₁₋₃ alkylene-S(O)₂-alkyl, and with the further proviso thatwhen Z is a bond or C₁₋₅ alkylene and R₂ is —X—Y—R₄ and Y is —N(R₈)-Q-,then Q is other than —C(R₆)—N(R₈)—W—;

or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a compound of theFormula (IV):

wherein:

m is an integer from 1 to 5;

R′ is selected from the group consisting of:

-   -   hydroxy,    -   thiol,    -   —S(O)₀₋₂-alkyl,    -   —S(O)₂—NH—R₉,    -   alkoxy,    -   —O—C₁₋₃ alkylene-S(O)₂-alkyl,    -   —N(R₉)₂, and    -   —NH-Q-R₄;

Z is selected from the group consisting of:

-   -   a bond,    -   C₁₋₅ alkylene,

A′ is selected from the group consisting of:

-   -   —O—,    -   —C(O)—,    -   —N(R₈)—,    -   —N(Q-R₄)—,    -   —N(C₁₋₅ alkylene-NH-Q-R₄)—,    -   —N(C₁₋₅ alkylene-W—NH—R₈)—, and    -   —S(O)₀₋₂—;

R₂ is selected from the group consisting of:

-   -   —R₄,    -   —X—R₄,    -   —X—Y—R₄, and    -   —X—R₅;

R_(A′) and R_(B′) are each independently selected from the groupconsisting of:

-   -   hydrogen,    -   halogen,    -   alkyl,    -   alkenyl,    -   alkoxy,    -   alkylthio, and    -   —N(R₉)₂;

X is selected from the group consisting of alkylene, alkenylene,alkynylene, arylene, heteroarylene, and heterocyclylene wherein thealkylene, alkenylene, and alkynylene groups can be optionallyinterrupted or terminated with arylene, heteroarylene, orheterocyclylene, and optionally interrupted by one or more —O— groups;

Y is selected from the group consisting of:

-   -   —S(O)₀₋₂—,    -   —S(O)₂—N(R₈)—,    -   —C(R₆)—,    -   —C(R₆)—O—,    -   —O—C(R₆)—,    -   —O—C(O)—O—,    -   —N(R₈)-Q-,    -   —C(R₆)—N(R₈)—,    -   —O—C(R₆)—N(R₈)—,    -   —C(R₆)—N(OR₉)—,

R₄ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl, wherein the alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted orsubstituted by one or more substituents independently selected from thegroup consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy,halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy,arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy,heterocyclyl, amino, acetylamino, alkylamino, dialkylamino,(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl,and heterocyclyl, oxo;

R₅ is selected from the group consisting of:

R₆ is selected from the group consisting of ═O and ═S;

R₇ is C₂₋₇ alkylene;

R₈ is selected from the group consisting of hydrogen, alkyl,alkoxyalkylenyl, and arylalkylenyl;

R₉ is selected from the group consisting of hydrogen and alkyl;

R₁₀ is C₃₋₈ alkylene;

R₁₁ is selected from the group consisting of hydrogen, alkyl, halogen,and trifluoromethyl;

R₁₂ is selected from the group consisting of hydrogen, alkyl, phenyl,2-pyridyl, 3-pyridyl, and 4-pyridyl;

A is selected from the group consisting of —O—, —C(O)—, —S(O)₀₋₂—,—CH₂—, and —N(R₄)—;

Q is selected from the group consisting of a bond, —C(R₆)—,—C(R₆)—C(R₆), —S(O)₂—, —C(R₆)—N(R₈)—W—, —S(O)₂—N(R₈)—, —C(R₆)—O—, and—C(R₆)—N(OR₉)—;

V is selected from the group consisting of —C(R₆)—, —O—C(R₆)—,—N(R₈)—C(R₆)—, and —S(O)₂—;

W is selected from the group consisting of a bond, —C(O)—, and —S(O)₂—;and

a and b are independently integers from 1 to 6 with the proviso that a+bis ≦7;

with the proviso that when Z is a bond or C₁₋₅ alkylene and R₂ is—X—Y—R₄ and Y is —N(R₈)-Q-, then Q is other than —C(R₆)—N(R₈)—W—;

or a pharmaceutically acceptable salt thereof.

In another embodiment, there is provided a compound of the Formula (V):

wherein:

m is an integer from 1 to 5;

p is an integer from 0 to 3;

R′ is selected from the group consisting of:

-   -   hydroxy,    -   thiol,    -   —S(O)₀₋₂-alkyl,    -   —S(O)₂—NH—R₉,    -   alkoxy,    -   —O—C₁₋₃ alkylene-S(O)₂-alkyl,    -   —N(R₉)₂, and    -   —NH-Q-R₄;

Z is selected from the group consisting of:

-   -   a bond,    -   C₁₋₅ alkylene,

A′ is selected from the group consisting of:

-   -   —O—,    -   —C(O)—,    -   —N(R₈)—,    -   —N(Q-R₄)—,    -   —N(C₁₋₅ alkylene-NH-Q-R₄)—,    -   —N(C₁₋₅ alkylene-W—NH—R₈)—, and    -   —S(O)₀₋₂—;

R₂ is selected from the group consisting of:

-   -   —R₄,    -   —X—R₄,    -   —X—Y—R₄, and    -   —X—R₅;

R is selected from the group consisting of:

-   -   halogen,    -   hydroxy,    -   alkyl,    -   alkenyl,    -   haloalkyl,    -   alkoxy,    -   alkylthio, and    -   —N(R₉)₂;

X is selected from the group consisting of alkylene, alkenylene,alkynylene, arylene, heteroarylene, and heterocyclylene wherein thealkylene, alkenylene, and alkynylene groups can be optionallyinterrupted or terminated with arylene, heteroarylene, orheterocyclylene, and optionally interrupted by one or more —O— groups;

Y is selected from the group consisting of:

-   -   —S(O)₀₋₂—,    -   —S(O)₂—N(R₈)—,    -   —C(R₆)—,    -   —C(R₆)—O—,    -   —O—C(R₆)—,    -   —O—C(O)—O—,    -   —N(R₈)-Q-,    -   —C(R₆)—N(R₈)—,    -   —O—C(R₆)—N(R₈)—,    -   —C(R₆)—N(OR₉)—,

R₄ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl, wherein the alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted orsubstituted by one or more substituents independently selected from thegroup consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy,halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy,arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy,heterocyclyl, amino, acetylamino, alkylamino, dialkylamino,(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl,and heterocyclyl, oxo;

R₅ is selected from the group consisting of:

R₆ is selected from the group consisting of ═O and ═S;

R₇ is C₂₋₇ alkylene;

R₈ is selected from the group consisting of hydrogen, alkyl,alkoxyalkylenyl, and arylalkylenyl;

R₉ is selected from the group consisting of hydrogen and alkyl;

R₁₀ is C₃₋₈ alkylene;

R₁₁ is selected from the group consisting of hydrogen, alkyl, halogen,and trifluoromethyl;

R₁₂ is selected from the group consisting of hydrogen, alkyl, phenyl,2-pyridyl, 3-pyridyl, and 4-pyridyl;

A is selected from the group consisting of —O—, —C(O)—, —S(O)₀₋₂—,—CH₂—, and —N(R₄)—;

Q is selected from the group consisting of a bond, —C(R₆)—,—C(R₆)—C(R₆), —S(O)₂—, —C(R₆)—N(R₈)—W—, —S(O)₂—N(R₈)—, —C(R₆)—O—, and—C(R₆)—N(OR₉)—;

V is selected from the group consisting of —C(R₆)—, —O—C(R₆)—,—N(R₈)—C(R₆)—, and —S(O)₂—;

W is selected from the group consisting of a bond, —C(O)—, and —S(O)₂—;and

a and b are independently integers from 1 to 6 with the proviso that a+bis ≦7;

with the proviso that when Z is a bond or C₁₋₅ alkylene then R′ is otherthan —O—C₁₋₃ alkylene-S(O)₂-alkyl, and with the further proviso thatwhen Z is a bond or C₁₋₅ alkylene and R₂ is —X—Y—R₄ and Y is —N(R₈)-Q-,then Q is other than —C(R₆)—N(R₈)—W—;

or a pharmaceutically acceptable salt thereof.

In another embodiment, there is provided a compound of the Formula (VI):

wherein:

m is an integer from 1 to 5;

p is an integer from 0 to 3;

R′ is selected from the group consisting of:

-   -   hydroxy,    -   thiol,    -   —S(O)₀₋₂-alkyl,    -   —S(O)₂—NH—R₉,    -   alkoxy,    -   —O—C₁₋₃ alkylene-S(O)₂-alkyl,    -   —N(R₉)₂, and    -   —NH-Q-R₄;

Z is selected from the group consisting of:

-   -   a bond,    -   C₁₋₅ alkylene,

A′ is selected from the group consisting of:

-   -   —O—,    -   —C(O)—,    -   —N(R₈)—,    -   —N(Q-R₄)—,    -   —N(C₁₋₅ alkylene-NH-Q-R₄)—,    -   —N(C₁₋₅ alkylene-W—NH—R₈)—, and    -   —S(O)₀₋₂—;

R₂ is selected from the group consisting of:

-   -   —R₄,    -   —X—R₄,    -   —X—Y—R₄, and    -   —X—R₅;

R is selected from the group consisting of:

-   -   halogen,    -   hydroxy,    -   alkyl,    -   alkenyl,    -   haloalkyl,    -   alkoxy,    -   alkylthio, and    -   —N(R₉)₂;

X is selected from the group consisting of alkylene, alkenylene,alkynylene, arylene, heteroarylene, and heterocyclylene wherein thealkylene, alkenylene, and alkynylene groups can be optionallyinterrupted or terminated with arylene, heteroarylene, orheterocyclylene, and optionally interrupted by one or more —O— groups;

Y is selected from the group consisting of:

-   -   —S(O)₀₋₂—,    -   —S(O)₂—N(R₈)—,    -   —C(R₆)—,    -   —C(R₆)—O—,    -   —O—C(R₆)—,    -   —O—C(O)—O—,    -   —N(R₈)-Q-,    -   —C(R₆)—N(R₈)—,    -   —O—C(R₆)—N(R₈)—,    -   —C(R₆)—N(OR₉)—,

R₄ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl, wherein the alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted orsubstituted by one or more substituents independently selected from thegroup consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy,halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy,arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy,heterocyclyl, amino, acetylamino, alkylamino, dialkylamino,(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl,and heterocyclyl, oxo;

R₅ is selected from the group consisting of:

R₆ is selected from the group consisting of ═O and ═S;

R₇ is C₂₋₇ alkylene;

R₈ is selected from the group consisting of hydrogen, alkyl,alkoxyalkylenyl, and arylalkylenyl;

R₉ is selected from the group consisting of hydrogen and alkyl;

R₁₀ is C₃₋₈ alkylene;

R₁₁ is selected from the group consisting of hydrogen, alkyl, halogen,and trifluoromethyl;

R₁₂ is selected from the group consisting of hydrogen, alkyl, phenyl,2-pyridyl, 3-pyridyl, and 4-pyridyl;

A is selected from the group consisting of —O—, —C(O)—, —S(O)₀₋₂—,—CH₂—, and —N(R₄)—;

Q is selected from the group consisting of a bond, —C(R₆)—,—C(R₆)—C(R₆), —S(O)₂—, —C(R₆)—N(R₈)—W—, —S(O)₂—N(R₈)—, —C(R₆)—O—, and—C(R₆)—N(OR₉)—;

V is selected from the group consisting of —C(R₆)—, —O—C(R₆)—,—N(R₈)—C(R₆)—, and —S(O)₂—;

W is selected from the group consisting of a bond, —C(O)—, and —S(O)₂—;and

a and b are independently integers from 1 to 6 with the proviso that a+bis ≦7;

with the proviso that when Z is a bond or C₁₋₅ alkylene then R′ is otherthan —O—C₁₋₃ alkylene-S(O)₂-alkyl, and with the further proviso thatwhen Z is a bond or C₁₋₅ alkylene and R₂ is —X—Y—R₄ and Y is —N(R₈)-Q-,then Q is other than —C(R₆)—N(R₈)—W—;

or a pharmaceutically acceptable salt thereof.

In another embodiment, there is provided a compound of the Formula(VII):

wherein:

Z is a bond or C₁₋₃ alkylene; and

R₂ is selected from the group consisting of hydrogen, C₁₋₄ alkyl,HO—C₁₋₄ alkylenyl and C₁₋₄ alkyl-O—C₁₋₄ alkylenyl;

or a pharmaceutically acceptable salt thereof.

In another embodiment, there is provided a compound of the Formula(VIII):

wherein R₂ is selected from the group consisting of hydrogen, C₁₋₄alkyl, HO—C₁₋₄ alkylenyl and C₁₋₄ alkyl-O—C₁₋₄ alkylenyl; or apharmaceutically acceptable salt thereof.

In another embodiment, there is provided a compound of the Formula (IX):

wherein R₂ is selected from the group consisting of hydrogen, C₁₋₄alkyl,HO—C₁₋₄ alkylenyl and C₁₋₄ alkyl-O—C₁₋₄ alkylenyl; or a pharmaceuticallyacceptable salt thereof.

In another embodiment, there is provided a compound (which is a prodrug)of the Formula (X):

wherein:

m is an integer from 1 to 5;

R′ is selected from the group consisting of:

-   -   hydroxy,    -   thiol,    -   —S(O)₀₋₂-alkyl,    -   —S(O)₂—NH—R₉,    -   alkoxy,    -   —O—C₁₋₃ alkylene-S(O)₂-alkyl,    -   —N(R₉)₂, and    -   —NH-Q-R₄;

Z is selected from the group consisting of:

-   -   a bond,    -   C₁₋₅ alkylene,

A′ is selected from the group consisting of:

-   -   —O—,    -   —C(O)—,    -   —N(R₈)—,    -   —N(Q-R₄)—,    -   —N(C₁₋₅ alkylene-NH-Q-R₄)—,    -   —N(C₁₋₅ alkylene-W—NH—R₈)—, and    -   —S(O)₀₋₂—;

R₂ is selected from the group consisting of:

-   -   —R₄,    -   —X—R₄,    -   —X—Y—R₄, and    -   —X—R₅;

R_(A) and R_(B) are each independently selected from the groupconsisting of:

-   -   hydrogen,    -   halogen,    -   alkyl,    -   alkenyl,    -   alkoxy,    -   alkylthio, and    -   —N(R₉)₂;

or when taken together, R_(A) and R_(B) form a fused aryl ring orheteroaryl ring containing one heteroatom selected from the groupconsisting of N and S wherein the aryl or heteroaryl ring isunsubstituted or substituted by one or more R groups;

or when taken together, R_(A) and R_(B) form a fused 5 to 7 memberedsaturated ring, optionally containing one heteroatom selected from thegroup consisting of N and S, and unsubstituted or substituted by one ormore R groups;

R is selected from the group consisting of:

-   -   halogen,    -   hydroxy,    -   alkyl,    -   alkenyl,    -   haloalkyl,    -   alkoxy,    -   alkylthio, and    -   —N(R₉)₂;

X is selected from the group consisting of alkylene, alkenylene,alkynylene, arylene, heteroarylene, and heterocyclylene wherein thealkylene, alkenylene, and alkynylene groups can be optionallyinterrupted or terminated with arylene, heteroarylene, orheterocyclylene, and optionally interrupted by one or more —O— groups;

Y is selected from the group consisting of:

-   -   —S(O)₀₋₂—,    -   —S(O)₂—N(R₈)—,    -   —C(R₆)—,    -   —C(R₆)—O—,    -   —O—C(R₆)—,    -   —O—C(O)—O—,    -   —N(R₈)-Q-,    -   —C(R₆)—N(R₈)—,    -   —O—C(R₆)—N(R₈)—,    -   —C(R₆)—N(OR₉)—,

R₄ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl, wherein the alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted orsubstituted by one or more substituents independently selected from thegroup consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy,halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy,arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy,heterocyclyl, amino, acetylamino, alkylamino, dialkylamino,(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl,and heterocyclyl, oxo;

R₅ is selected from the group consisting of:

R₆ is selected from the group consisting of ═O and ═S;

R₇ is C₂₋₇ alkylene;

R₈ is selected from the group consisting of hydrogen, alkyl,alkoxyalkylenyl, and arylalkylenyl;

R₉ is selected from the group consisting of hydrogen and alkyl;

R₁₀ is C₃₋₈ alkylene;

R₁₁ is selected from the group consisting of hydrogen, alkyl, halogen,and trifluoromethyl;

R₁₂ is selected from the group consisting of hydrogen, alkyl, phenyl,2-pyridyl, 3-pyridyl, and 4-pyridyl;

A is selected from the group consisting of —O—, —C(O)—, —S(O)₀₋₂—,—CH₂—, and —N(R₄)—;

Q is selected from the group consisting of a bond, —C(R₆)—,—C(R₆)—C(R₆), —S(O)₂—, —C(R₆)—N(R₈)—W—, —S(O)₂—N(R₈)—, —C(R₆)—O—, and—C(R₆)—N(OR₉)—;

V is selected from the group consisting of —C(R₆)—, —O—C(R₆)—,—N(R₈)—C(R₆)—, and —S(O)₂—;

W is selected from the group consisting of a bond, —C(O)—, and —S(O)₂—;and

a and b are independently integers from 1 to 6 with the proviso that a+bis ≦7;

G is selected from the group consisting of:

-   -   —C(O)—R″,    -   α-aminoacyl,    -   α-aminoacyl-α-aminoacyl,    -   —C(O)—O—R″,    -   —C(O)—N(R′″)R″,    -   —C(═NY′)—R″,    -   —CH(OH)—C(O)—OY′,    -   —CH(OC₁₋₄ alkyl)Y₀,    -   —CH₂Y₁, and    -   —CH(CH₃)Y₁;

R″ and R′″ are independently selected from the group consisting of C₁₋₁₀alkyl, C₃₋₇ cycloalkyl, and benzyl, each of which may be unsubstitutedor substituted by one or more substitutents selected from the groupconsisting of halogen, hydroxy, nitro, cyano, carboxy, C₁₋₆ alkyl, C₁₋₄alkoxy, aryl, heteroaryl, arylC₁₋₄ alkylenyl, heteroarylC₁₋₄ alkylenyl,haloC₁₋₄ alkylenyl, haloC₁₋₄ alkoxy, —O—C(O)—CH₃, —C(O)—O—CH₃,—C(O)—NH₂, —O—CH₂—C(O)—NH₂, —NH₂, and —S(O)₂—NH₂, with the proviso thatR′″ can also be hydrogen;

α-aminoacyl is an acyl group derived from an amino acid selected fromthe group consisting of racemic, D-, and L-amino acids;

Y′ is selected from the group consisting of hydrogen, C₁₋₆ alkyl, andbenzyl;

Y₀ is selected from the group consisting of C₁₋₆ alkyl, carboxyC₁₋₆alkylenyl, aminoC₁₋₄alkylenyl, mono-N—C₁₋₆ alkylaminoC₁₋₄ alkylenyl, anddi-N,N—C₁₋₆ alkylaminoC₁₋₄ alkylenyl;

Y₁ is selected from the group consisting of mono-N—C₁₋₆ alkylamino,di-N,N—C₁₋₆ alkylamino, morpholin-4-yl, piperidin-1-yl, pyrrolidin-1-yl,and 4-C₁₋₄ alkylpiperazin-1-yl;

with the proviso that when Z is a bond or C₁₋₅ alkylene then R′ is otherthan —O—C₁₋₃ alkylene-S(O)₂-alkyl, and with the further proviso thatwhen Z is a bond or C₁₋₅ alkylene and R₂ is —X—Y—R₄ and Y is —N(R₈)-Q-,then Q is other than —C(R₆)—N(R₈)—W—;

or a pharmaceutically acceptable salt thereof.

In another embodiment, there is provided a compound of the Formula (XI):

wherein:

R′ is selected from the group consisting of:

-   -   hydroxy,    -   thiol,    -   —S(O)₀₋₂-alkyl,    -   —S(O)₂—NH—R₉,    -   alkoxy,    -   —O—C₁₋₃ alkylene-S(O)₂-alkyl,    -   —N(R₉)₂, and    -   —NH-Q-R₄;

R₂ is selected from the group consisting of:

-   -   —R₄,    -   —X—R₄,    -   —X—Y—R₄, and    -   —X—R₅;

R_(A) and R_(B) are each independently selected from the groupconsisting of:

-   -   hydrogen,    -   halogen,    -   alkyl,    -   alkenyl,    -   alkoxy,    -   alkylthio, and    -   —N(R₉)₂;

or when taken together, R_(A) and R_(B) form a fused aryl ring orheteroaryl ring containing one heteroatom selected from the groupconsisting of N and S wherein the aryl or heteroaryl ring isunsubstituted or substituted by one or more R groups;

or when taken together, R_(A) and R_(B) form a fused 5 to 7 memberedsaturated ring, optionally containing one heteroatom selected from thegroup consisting of N and S, and unsubstituted or substituted by one ormore R groups;

R is selected from the group consisting of:

-   -   halogen,    -   hydroxy,    -   alkyl,    -   alkenyl,    -   haloalkyl,    -   alkoxy,    -   alkylthio, and    -   —N(R₉)₂;

X is selected from the group consisting of alkylene, alkenylene,alkynylene, arylene, heteroarylene, and heterocyclylene wherein thealkylene, alkenylene, and alkynylene groups can be optionallyinterrupted or terminated with arylene, heteroarylene, orheterocyclylene, and optionally interrupted by one or more —O— groups;

Y is selected from the group consisting of:

-   -   —S(O)₀₋₂—,    -   —S(O)₂—N(R₈)—,    -   —C(R₆)—,    -   —C(R₆)—O—,    -   —O—C(R₆)—,    -   —O—C(O)—O—,    -   —N(R₈)-Q-,    -   —C(R₆)—N(R₈)—,    -   —O—C(R₆)—N(R₈)—,    -   —C(R₆)—N(OR₉)—,

R₄ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl, wherein the alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted orsubstituted by one or more substituents independently selected from thegroup consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy,halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy,arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy,heterocyclyl, amino, acetylamino, alkylamino, dialkylamino,(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl,and heterocyclyl, oxo;

R₅ is selected from the group consisting of:

R₆ is selected from the group consisting of ═O and ═S;

R₇ is C₂₋₇ alkylene;

R₈ is selected from the group consisting of hydrogen, alkyl,alkoxyalkylenyl, and arylalkylenyl;

R₉ is selected from the group consisting of hydrogen and alkyl;

R₁₀ is C₃₋₈ alkylene;

A is selected from the group consisting of —O—, —C(O)—, —S(O)₀₋₂—,—CH₂—, and —N(R₄)—;

Q is selected from the group consisting of a bond, —C(R₆)—,—C(R₆)—C(R₆), —S(O)₂—, —C(R₆)—N(R₈)—W—, —S(O)₂—N(R₈)—, —C(R₆)—O—, and—C(R₆)—N(OR₉)—;

V is selected from the group consisting of —C(R₆)—, —O—C(R₆)—,—N(R₈)—C(R₆)—, and —S(O)₂—;

W is selected from the group consisting of a bond, —C(O)—, and —S(O)₂—;and

a and b are independently integers from 1 to 6 with the proviso that a+bis ≦7;

or a pharmaceutically acceptable salt thereof.

In another embodiment, there is provided a compound of the Formula(XII):

wherein:

R′ is selected from the group consisting of:

-   -   hydroxy,    -   thiol,    -   —S(O)₀₋₂-alkyl,    -   —S(O)₂—NH—R₉,    -   alkoxy,    -   —O—C₁₋₃ alkylene-S(O)₂-alkyl,    -   —N(R₉)₂, and    -   —NH-Q-R₄;

R₂ is selected from the group consisting of:

-   -   —R₄,    -   —X—R₄,    -   —X—Y—R₄, and    -   —X—R₅;

R_(A) and R_(B) are each independently selected from the groupconsisting of:

-   -   hydrogen,    -   halogen,    -   alkyl,    -   alkenyl,    -   alkoxy,    -   alkylthio, and    -   —N(R₉)₂;

or when taken together, R_(A) and R_(B) form a fused aryl ring orheteroaryl ring containing one heteroatom selected from the groupconsisting of N and S wherein the aryl or heteroaryl ring isunsubstituted or substituted by one or more R groups;

or when taken together, R_(A) and R_(B) form a fused 5 to 7 memberedsaturated ring, optionally containing one heteroatom selected from thegroup consisting of N and S, and unsubstituted or substituted by one ormore R groups;

R is selected from the group consisting of:

-   -   halogen,    -   hydroxy,    -   alkyl,    -   alkenyl,    -   haloalkyl,    -   alkoxy,    -   alkylthio, and    -   —N(R₉)₂;

X is selected from the group consisting of alkylene, alkenylene,alkynylene, arylene, heteroarylene, and heterocyclylene wherein thealkylene, alkenylene, and alkynylene groups can be optionallyinterrupted or terminated with arylene, heteroarylene, orheterocyclylene, and optionally interrupted by one or more —O— groups;

Y is selected from the group consisting of:

-   -   —S(O)₀₋₂—,    -   —S(O)₂—N(R₈)—,    -   —C(R₆)—,    -   —C(R₆)—O—,    -   —O—C(R₆)—,    -   —O—C(O)—O—,    -   —N(R₈)-Q-,    -   —C(R₆)—N(R₈)—,    -   —O—C(R₆)—N(R₈)—,    -   —C(R₆)—N(OR₉)—,

R₄ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl, wherein the alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted orsubstituted by one or more substituents independently selected from thegroup consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy,halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy,arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy,heterocyclyl, amino, acetylamino, alkylamino, dialkylamino,(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl,and heterocyclyl, oxo;

R₅ is selected from the group consisting of:

R₆ is selected from the group consisting of ═O and ═S;

R₇ is C₂₋₇ alkylene;

R₈ is selected from the group consisting of hydrogen, alkyl,alkoxyalkylenyl, and arylalkylenyl;

R₉ is selected from the group consisting of hydrogen and alkyl;

R₁₀ is C₃₋₈ alkylene;

A is selected from the group consisting of —O—, —C(O)—, —S(O)₀₋₂—,—CH₂—, and —N(R₄)—;

Q is selected from the group consisting of a bond, —C(R₆)—,—C(R₆)—C(R₆), —S(O)₂—, —C(R₆)—N(R₈)—W—, —S(O)₂—N(R₈)—, —C(R₆)—O—, and—C(R₆)—N(OR₉)—;

V is selected from the group consisting of —C(R₆)—, —O—C(R₆)—,—N(R₈)—C(R₆)—, and —S(O)₂—;

W is selected from the group consisting of a bond, —C(O)—, and —S(O)₂—;and

a and b are independently integers from 1 to 6 with the proviso that a+bis ≦7;

or a pharmaceutically acceptable salt thereof.

For any of the compounds presented herein, each one of the followingvariables (e.g., Z, X, Y, R, R′, R_(A), R_(B), R_(A′), R_(B′), R₂, Q, W,m, n, p, G, and so on) in any of its embodiments can be combined withany one or more of the other variables in any of their embodiments andassociated with any one of the formulas described herein, as would beunderstood by one of skill in the art. Each of the resultingcombinations of variables is an embodiment of the present invention.

For certain embodiments, m is an integer from 1 to 5. For certainembodiments, m is 1, 2, or 3. For certain embodiments, m is 1 or 2.Preferably, m is 1.

For certain embodiments, n is an integer from 0 to 4. Preferably, n is0.

For certain embodiments, p is an integer from 0 to 3. Preferably, p is0.

For certain embodiments, R′ is selected from the group consisting ofhydroxy, thiol, —S(O)₀₋₂-alkyl, —S(O)₂—NH—R₉, alkoxy, —O—C₁₋₃alkylene-S(O)₂-alkyl, —N(R₉)₂, and —NH-Q-R₄. For certain embodiments,particularly when Z is a bond or C₁₋₅ alkylene, R′ is other than —O—C₁₋₃alkylene-S(O)₂-alkyl.

For certain embodiments, R′ is selected from the group consisting ofhydroxy, methoxy, and amino. For certain embodiments, R′ is selectedfrom the group consisting of hydroxy and methoxy. For certainembodiments R′ is hydroxy. For certain embodiments, R′ is —O—C₁₋₃alkylene-S(O)₂-alkyl. For certain alternative embodiments, R′ isselected from the group consisting of —NH₂ and —NH-Q-R₄. In suchembodiments, preferably Q is selected from the group consisting of—C(O)—, —S(O)₂—, —C(O)—O—, and —C(O)—NH—, and R₄ is selected from thegroup consisting of alkyl and alkoxyalkylene. Alternatively, in suchembodiments, preferably Q is selected from the group consisting of—C(O)—, —C(O)—O—, —S(O)₂—, and —C(R₆)—N(R₈)—, R₈ is selected fromhydrogen and C₁₋₄ alkyl, and R₄ is alkyl, aryl, arylalkylene,heteroaryl, and heterocyclyl, wherein the aryl group can beunsubstituted or substituted by acetylamino, alkyl, alkoxy, cyano, andhalogen. More preferably, Q is selected from the group consisting of—C(O)—, —S(O)₂—, —C(O)—O—, and —C(O)—NH—, and R₄ is selected from thegroup consisting of alkyl and alkoxyalkylene.

For certain embodiments, Z is selected from the group consisting of abond, C₁₋₅ alkylene,

For certain embodiments, Z is selected from the group consisting of abond and C₁₋₅ alkylene. In such embodiments, preferably R′ is other than—O—C₁₋₃ alkylene-S(O)₂-alkyl. Alternatively or additionally, in suchembodiments, preferably, when Z is a bond or C₁₋₅ alkylene and R₂ is—X—Y—R₄ and Y is —N(R₈)-Q-, then Q is other than —C(R₆)—N(R₈)—W—

For certain embodiments, Z is selected from the group consisting of abond and C₁₋₃ alkylene.

For certain alternative embodiments, Z is —(CH₂)₀₋₁-A′-(CH₂)₀₋₁—. Insome of these embodiments Z is —(CH₂)-A′-(CH₂)—. In some embodiments,preferably, A′ is —O—. In some embodiments, preferably, A′ is —S(O)₂—.In some embodiments, preferably, A′ is selected from the groupconsisting of —N(R₈)— and —N(Q-R₄)—. In some embodiments, In someembodiments, preferably, A′ is selected from the group consisting of—O—, —N(R₈)—, and —N(Q-R₄)—. In such embodiments, preferably, Q isselected from the group consisting of —C(O)—, —C(O)—O—, —S(O)₂—, and—C(R₆)—N(R₈)—, wherein, preferably, R₅ is selected from hydrogen andC₁₋₄ alkyl. In such embodiments, preferably, R₄ is selected from thegroup consisting of alkyl, aryl, arylalkylene, heteroaryl, andheterocyclyl, wherein the aryl group can be unsubstituted or substitutedby acetylamino, alkyl, alkoxy, cyano, and halogen. In such embodiments,more preferably, Q is —S(O)₂— and R₄ is C₁₋₄ alkyl.

For certain embodiments, Z is selected from the group consisting of abond, —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, and —CH₂—O—CH₂—. For certainembodiments Z is —CH₂CH₂CH₂— or —CH₂—O—CH₂—.

For certain embodiments, R₂ is selected from the group consisting of—R₄, —X—R₄, —X—Y—R₄, and —X—R₅. For certain embodiments, R₂ is —X—Y—R₄.

For certain embodiments, R₂ is selected from the group consisting ofhydrogen, alkyl, alkoxyalkylenyl, hydroxyalkylenyl, and —X—Y—R₄ whereinX is C₁₋₂ alkylene; Y is selected from the group consisting of—S(O)₀₋₂—, —S(O)₂—N(R₈)—, —C(R₆)—, —C(R₆)—O—, —O—C(R₆)—, —O—C(O)—O—,—N(R₈)-Q-, —C(R₆)—N(R₈)—, —O—C(R₆)—N(R₈)—, and —C(R₆)—N(OR₉)—; and R₄ isalkyl.

For certain embodiments, R₂ is selected from the group consisting ofhydrogen, alkyl, alkoxyalkylenyl, and —X—Y—R₄ wherein X is C₁₋₂alkylene; Y is selected from the group consisting of —S(O)₀₋₂—,—S(O)₂—N(R₈)—, —C(R₆)—, —C(R₆)—O—, —O—C(R₆)—, —O—C(O)—O—, —N(R₈)-Q-,—C(R₆)—N(R₈)—, —O—C(R₆)—N(R₈)—, and —C(R₆)—N(OR₉)—; and R₄ is alkyl.Preferably, R₂ is selected from the group consisting of hydrogen, C₁₋₄alkyl, and C₁₋₄ alkyl-O—C₁₋₄ alkylenyl. For certain embodiments, R₂ ishydrogen or C₁₋₄ alkyl. For certain embodiments, R₂ is C₁₋₄ alkyl. Morepreferably, R₂ is selected from the group consisting of hydrogen,methyl, ethyl, n-propyl, n-butyl, ethoxymethyl, and 2-methoxyethyl. Forcertain embodiments, R₂ is selected from the group consisting ofhydrogen, methyl, ethyl, n-propyl, and n-butyl.

For certain embodiments, R₂ is HO—C₁₋₄ alkylenyl or C₁₋₄ alkyl-O—C₁₋₄alkylenyl. For certain embodiments, R₂ is selected from the groupconsisting of hydroxymethyl, 2-hydroxyethyl, ethoxymethyl, and2-methoxyethyl. For certain embodiments, R₂ is selected from the groupconsisting of hydrogen, C₁₋₄ alkyl, HO—C₁₋₄ alkylenyl and C₁₋₄alkyl-O—C₁₋₄ alkylenyl.

For certain embodiments, R_(A′) and R_(B′) are each independentlyselected from the group consisting of hydrogen, halogen, alkyl, alkenyl,alkoxy, alkylthio, and —N(R₉)₂.

For certain embodiments, R_(A′) and R_(B′) are independently hydrogen oralkyl. Preferably, R_(A′) and R_(B′) are both methyl.

For certain embodiments, X is selected from the group consisting ofalkylene, alkenylene, alkynylene, arylene, heteroarylene, andheterocyclylene wherein the alkylene, alkenylene, and alkynylene groupscan be optionally interrupted or terminated with arylene, heteroarylene,or heterocyclylene, and optionally interrupted by one or more —O—groups. For certain embodiments, particularly in —X—Y—R₄, X is C₁₋₂alkylene.

For certain embodiments, Y is selected from the group consisting of—S(O)₀₋₂—, —S(O)₂—N(R₈)—, —C(R₆)—, —C(R₆)—O—, —O—C(R₆)—, —O—C(O)—O—,—N(R₈)-Q-, —C(R₆)—N(R₈)—, —O—C(R₆)—N(R₈)—, —C(R₆)—N(OR₉)—,

For certain embodiments, Y is selected from the group consisting of—S(O)₀₋₂—, —S(O)₂—N(R₈)—, —C(R₆)—, —C(R₆)—O—, —O—C(R₆)—, —O—C(O)—O—,—N(R₈)-Q-, —C(R₆)—N(R₈)—, —O—C(R₆)—N(R₈)—, and —C(R₆)—N(OR₉)—. Forcertain embodiments, Y is —N(R₈)-Q-.

For certain embodiments, R_(A) and R_(B) are each independently selectedfrom the group consisting of hydrogen, halogen, alkyl, alkenyl, alkoxy,alkylthio, and —N(R₉)₂. Alternatively, for certain embodiments, whentaken together, R_(A) and R_(B) form a fused aryl ring or heteroarylring containing one heteroatom selected from the group consisting of Nand S wherein the aryl or heteroaryl ring is unsubstituted orsubstituted by one or more R groups. Alternatively, when taken together,R_(A) and R_(B) form a fused 5 to 7 membered saturated ring, optionallycontaining one heteroatom selected from the group consisting of N and S,and unsubstituted or substituted by one or more R groups. For certainembodiments, R_(A) and R_(B) join to form a fused benzene ring. Forcertain embodiments, R_(A) and R_(B) join to form a fused pyridine ring.

For certain embodiments, R is selected from the group consisting ofhalogen, hydroxy, alkyl, alkenyl, haloalkyl, alkoxy, alkylthio, and—N(R₉)₂.

For certain embodiments, R₄ is selected from the group consisting ofhydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl,aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl,heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl, whereinthe alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl,alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted orsubstituted by one or more substituents independently selected from thegroup consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy,halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy,arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy,heterocyclyl, amino, acetylamino, alkylamino, dialkylamino,(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl,and heterocyclyl, oxo.

For certain embodiments, R₄ is alkyl, aryl, arylalkylene, heteroaryl,and heterocyclyl, wherein the aryl group can be unsubstituted orsubstituted by acetylamino, alkyl, alkoxy, cyano, and halogen. Forcertain embodiments, R₄ is selected from the group consisting of alkyland alkoxyalkylene.

For certain embodiments, R₄ is alkyl. For certain embodiments, R₄ ismethyl, ethyl, isopropyl, or phenyl. For certain embodiments, R₄ ismethyl or ethyl.

For certain embodiments, R₅ is selected from the group consisting of

For certain embodiments, R₆ is selected from the group consisting of ═Oand ═S. For certain embodiments, R₆ is ═O.

For certain embodiments, R₇ is C₂₋₇ alkylene. For certain embodiments,particularly embodiments where Y is

R₇ is selected such that the total number of ring atoms is from 6 to 8.

For certain embodiments, R₈ is selected from the group consisting ofhydrogen, alkyl, alkoxyalkylenyl, and arylalkylenyl. For certainembodiments, R₈ is hydrogen or alkyl. For certain embodiments, R₈ isselected from hydrogen and C₁₋₄ alkyl.

For certain embodiments, R₉ is hydrogen or alkyl. For certainembodiments, R₉ is hydrogen.

For certain embodiments, R₁₀ is C₃₋₈ alkylene.

For certain embodiments, R₁₁ is selected from the group consisting ofhydrogen, alkyl, halogen, and trifluoromethyl.

For certain embodiments, R₁₂ is selected from the group consisting ofhydrogen, alkyl, phenyl, 2-pyridyl, 3-pyridyl, and 4-pyridyl.

For certain embodiments, A is selected from the group consisting of —O—,—C(O)—, —S(O)₀₋₂—, —CH₂—, and —N(R₄)—.

For certain embodiments, A′ is selected from the group consisting of—O—, —C(O)—, —N(R₈)—, —N(Q-R₄)—, —N(C₁₋₅ alkylene-NH-Q-R₄)—, —N(C₁₋₅alkylene-W—NH—R₈)—, and —S(O)₀₋₂—. For certain embodiments, A′ is —O—,—N(R₈)—, or —N(Q-R₄)—. For certain embodiments, A′ is —O—. For certainembodiments, A′ is —S(O)₂—.

For certain embodiments, A′ is —N(R₈)— or —N(Q-R₄)—. In suchembodiments, preferably, Q is selected from the group consisting of—C(O)—, —C(O)—O—, —S(O)₂—, and —C(R₆)—N(R₈)—, R₅ is selected fromhydrogen and C₁₋₄ alkyl, and R₄ is selected from the group consisting ofalkyl, aryl, arylalkylene, heteroaryl, and heterocyclyl, wherein thearyl group can be unsubstituted or substituted by acetylamino, alkyl,alkoxy, cyano, and halogen. In such embodiments, more preferably, Q is—S(O)₂— and R₄ is C₁₋₄ alkyl.

For certain embodiments, Q is selected from the group consisting of abond, —C(R₆)—, —C(R₆)—C(R₆), —S(O)₂—, —C(R₆)—N(R₈)—W—, —S(O)₂—N(R₈)—,—C(R₆)—O—, and —C(R₆)—N(OR₉)—. For certain embodiments, Q is —C(O)—,—C(O)—O—, —S(O)₂—, or —C(R₆)—N(R₈)—. For certain embodiments, Q isselected from the group consisting of —C(O)—, —S(O)₂—, —C(O)—O—, and—C(O)—NH—. For certain embodiments, Q is a bond, —C(O)—, —S(O)₂—, or—C(O)—NH—. For certain embodiments, Q is —S(O)₂—.

For certain embodiments, particularly when Z is a bond or C₁₋₅ alkyleneand R₂ is —X—Y—R₄ and Y is —N(R₈)-Q-, then Q is other than—C(R₆)—N(R₈)—W—.

For certain embodiments, V is selected from the group consisting of—C(R₆)—, —O—C(R₆)—, —N(R₈)—C(R₆)—, and —S(O)₂—.

For certain embodiments, W is selected from the group consisting of abond, —C(O)—, and —S(O)₂—. For certain embodiments, W is a bond.

For certain embodiments, a and b are independently integers from 1 to 6with the proviso that a+b is ≦7.

For certain embodiments of the compounds of Formulas (I) through (IX),the —NH₂ group can be replaced by an —NH-G group to form prodrugs. Insuch embodiments, G is selected from the group consisting of: —C(O)—R″,α-aminoacyl, α-aminoacyl-α-aminoacyl, —C(O)—O—R″, —C(O)—N(R′″)R″,—C(═NY′)—R″, —CH(OH)—C(O)—OY′, —CH(OC₁₋₄ alkyl)Y₀, —CH₂Y₁, and—CH(CH₃)Y₁. In some of these embodiments G is —C(O)—R″, α-aminoacyl,α-aminoacyl-α-aminoacyl, or —C(O)—O—R″. Preferably, R″ and R′″ areindependently selected from the group consisting of C₁₋₁₀ alkyl, C₃₋₇cycloalkyl, and benzyl, each of which may be unsubstituted orsubstituted by one or more substitutents selected from the groupconsisting of halogen, hydroxy, nitro, cyano, carboxy, C₁₋₆ alkyl, C₁₋₄alkoxy, aryl, heteroaryl, arylC₁₋₄ alkylenyl, heteroarylC₁₋₄ alkylenyl,haloC₁₋₄ alkylenyl, haloC₁₋₄ alkoxy, —O—C(O)—CH₃, —C(O)—O—CH₃,—C(O)—NH₂, —O—CH₂—C(O)—NH₂, —NH₂, and —S(O)₂—NH₂. R′″ can also behydrogen. Preferably, α-aminoacyl is an acyl group derived from an aminoacid selected from the group consisting of racemic, D-, and L-aminoacids. Preferably, Y′ is selected from the group consisting of hydrogen,C₁₋₆ alkyl, and benzyl. Preferably, Y₀ is selected from the groupconsisting of C₁₋₆ alkyl, carboxyC₁₋₆ alkylenyl, aminoC₁₋₄ alkylenyl,mono-N—C₁₋₆ alkylaminoC₁₋₄ alkylenyl, and di-N,N—C₁₋₆ alkylaminoC₁₋₄alkylenyl. Preferably, Y₁ is selected from the group consisting ofmono-N—C₁₋₆ alkylamino, di-N,N—C₁₋₆ alkylamino, morpholin-4-yl,piperidin-1-yl, pyrrolidin-1-yl, and 4-C₁₋₄ alkylpiperazin-1-yl.

As used herein, the terms “alkyl, “alkenyl,” “alkynyl” and the prefix“alk-” are inclusive of both straight chain and branched chain groupsand of cyclic groups, e.g., cycloalkyl and cycloalkenyl. Unlessotherwise specified, these groups contain from 1 to 20 carbon atoms,with alkenyl groups containing from 2 to 20 carbon atoms, and alkynylgroups containing from 2 to 20 carbon atoms. In some embodiments, thesegroups have a total of up to 10 carbon atoms, up to 8 carbon atoms, upto 6 carbon atoms, up to 5 carbon atoms, or up to 4 carbon atoms. Cyclicgroups can be monocyclic or polycyclic and preferably have from 3 to 10ring carbon atoms. Exemplary cyclic groups include cyclopropyl,cyclopropylmethyl, cyclopentyl, cyclohexyl, adamantyl, and substitutedand unsubstituted bornyl, norbornyl, and norbornenyl.

Unless otherwise specified, “alkylene,” “alkenylene,” and “alkynylene”are the divalent forms of the “alkyl,” “alkenyl,” and “alkynyl” groupsdefined above. Likewise, “alkylenyl,” “alkenylenyl,” and “alkynylenyl”are the divalent forms of the “alkyl,” “alkenyl,” and “alkynyl” groupsdefined above. For example, an arylalkylenyl group comprises an alkylenemoiety to which an aryl group is attached.

The term “haloalkyl” is inclusive of groups that are substituted by oneor more halogen atoms, including perfluorinated groups. This is alsotrue of other groups that include the prefix “halo-”. Examples ofsuitable haloalkyl groups are chloromethyl, trifluoromethyl, and thelike.

The term “aryl” as used herein includes carbocyclic aromatic rings orring systems. Examples of aryl groups include phenyl, naphthyl,biphenyl, fluorenyl and indenyl.

The term “heteroatom” refers to the atoms O, S, or N.

The term “heteroaryl” includes aromatic rings or ring systems thatcontain at least one ring heteroatom (e.g., O, S, N). In someembodiments, the term “heteroaryl” includes a ring or ring system thatcontains 2 to 12 carbon atoms, 1 to 3 rings, 1 to 4 heteroatoms, and O,S, and/or N as the heteroatoms. Suitable heteroaryl groups includefuryl, thienyl, pyridyl, quinolinyl, isoquinolinyl, indolyl, isoindolyl,triazolyl, pyrrolyl, tetrazolyl, imidazolyl, pyrazolyl, oxazolyl,thiazolyl, benzofuranyl, benzothiophenyl, carbazolyl, benzoxazolyl,pyrimidinyl, benzimidazolyl, quinoxalinyl, benzothiazolyl,naphthyridinyl, isoxazolyl, isothiazolyl, purinyl, quinazolinyl,pyrazinyl, 1-oxidopyridyl, pyridazinyl, triazinyl, tetrazinyl,oxadiazolyl, thiadiazolyl, and so on.

The term “heterocyclyl” includes non-aromatic rings or ring systems thatcontain at least one ring heteroatom (e.g., O, S, N) and includes all ofthe fully saturated and partially unsaturated derivatives of the abovementioned heteroaryl groups. In some embodiments, the term“heterocyclyl” includes a ring or ring system that contains 2 to 12carbon atoms, 1 to 3 rings, 1 to 4 heteroatoms, and O, S, and N as theheteroatoms. Exemplary heterocyclic groups include pyrrolidinyl,tetrahydrofuranyl, morpholinyl, thiomorpholinyl,1,1-dioxothiomorpholinyl, piperidinyl, piperazinyl, thiazolidinyl,imidazolidinyl, isothiazolidinyl, tetrahydropyranyl, quinuclidinyl,homopiperidinyl (azepanyl), 1,4-oxazepanyl, homopiperazinyl(diazepanyl), 1,3-dioxolanyl, aziridinyl, azetidinyl,dihydroisoquinolin-(1H)-yl, octahydroisoquinolin-(1H)-yl,dihydroquinolin-(2H)-yl, octahydroquinolin-(2H)-yl,dihydro-1H-imidazolyl, 3-azabicyclo[3.2.2]non-3-yl, and the like.

The term “heterocyclyl” includes bicylic and tricyclic heterocyclic ringsystems. Such ring systems include fused and/or bridged rings and spirorings. Fused rings can include, in addition to a saturated or partiallysaturated ring, an aromatic ring, for example, a benzene ring. Spirorings include two rings joined by one spiro atom and three rings joinedby two spiro atoms.

When “heterocyclyl” contains a nitrogen atom, the point of attachment ofthe heterocyclyl group may be the nitrogen atom.

The terms “arylene,” “heteroarylene,” and “heterocyclylene” are thedivalent forms of the “aryl,” “heteroaryl,” and “heterocyclyl” groupsdefined above. Likewise, “arylenyl,” “heteroarylenyl,” and“heterocyclylenyl” are the divalent forms of the “aryl,” “heteroaryl,”and “heterocyclyl” groups defined above. For example, an alkylarylenylgroup comprises an arylene moiety to which an alkyl group is attached.

The term “fused aryl ring” includes fused carbocyclic aromatic rings orring systems. Examples of fused aryl rings include benzo, naphtho,fluoreno, and indeno.

The term “fused heteroaryl ring” includes the fused forms of 5 or 6membered aromatic rings that contain one heteroatom selected from S andN.

The term “fused 5 to 7 membered saturated ring” includes rings which arefully saturated except for the bond where the ring is fused.

When a group (or substituent or variable) is present more than once inany Formula described herein, each group (or substituent or variable) isindependently selected, whether explicitly stated or not. For example,for the formula —N(R₉)₂ each R₉ group is independently selected. Inanother example, when an R′ and an A′ group both contain an R₄ group,each R₄ group is independently selected.

The invention is inclusive of the compounds described herein in any oftheir pharmaceutically acceptable forms, including isomers (e.g.,diastereomers and enantiomers), salts, solvates, polymorphs, prodrugs,and the like. In particular, if a compound is optically active, theinvention specifically includes each of the compound's enantiomers aswell as racemic mixtures of the enantiomers. It should be understoodthat the term “compound” includes any or all of such forms, whetherexplicitly stated or not (although at times, “salts” are explicitlystated).

The term “prodrug” means a compound that can be transformed in vivo toyield an immune response modifying compound in any of the salt,solvated, polymorphic, or isomeric forms described above. The prodrug,itself, may be an immune response modifying compound in any of the salt,solvated, polymorphic, or isomeric forms described above. Thetransformation may occur by various mechanisms, such as through achemical (e.g., solvolysis or hydrolysis, for example, in the blood) orenzymatic biotransformation. A discussion of the use of prodrugs isprovided by T. Higuchi and W. Stella, “Pro-drugs as Novel DeliverySystems,” Vol. 14 of the A. C. S. Symposium Series, and in BioreversibleCarriers in Drug Design, ed. Edward B. Roche, American PharmaceuticalAssociation and Pergamon Press, 1987.

Preparation of the Compounds

Compounds of the invention may be synthesized by synthetic routes thatinclude processes analogous to those well known in the chemical arts,particularly in light of the description contained herein. The startingmaterials are generally available from commercial sources such asAldrich Chemicals (Milwaukee, Wis., USA) or are readily prepared usingmethods well known to those skilled in the art (e.g., prepared bymethods generally described in Louis F. Fieser and Mary Fieser, Reagentsfor Organic Synthesis, v. 1-19, Wiley, New York, (1967-1999 ed.); AlanR. Katritsky, Otto Meth-Cohn, Charles W. Rees, Comprehensive OrganicFunctional Group Transformations, v 1-6, Pergamon Press, Oxford,England, (1995); Barry M. Trost and Ian Fleming, Comprehensive OrganicSynthesis, v. 1-8, Pergamon Press, Oxford, England, (1991); orBeilsteins Handbuch der organischen Chemie, 4, Aufl. Ed.Springer-Verlag, Berlin, Germany, including supplements (also availablevia the Beilstein online database)).

For illustrative purposes, the reaction schemes depicted below providepotential routes for synthesizing the compounds of the present inventionas well as key intermediates. For more detailed description of theindividual reaction steps, see the EXAMPLES section below. Those skilledin the art will appreciate that other synthetic routes may be used tosynthesize the compounds of the invention. Although specific startingmaterials and reagents are depicted in the reaction schemes anddiscussed below, other starting materials and reagents can be easilysubstituted to provide a variety of derivatives and/or reactionconditions. In addition, many of the compounds prepared by the methodsdescribed below can be further modified in light of this disclosureusing conventional methods well known to those skilled in the art.

In the preparation of compounds of the invention it may sometimes benecessary to protect a particular functionality while reacting otherfunctional groups on an intermediate. The need for such protection willvary depending on the nature of the particular functional group and theconditions of the reaction step. Suitable amino protecting groupsinclude acetyl, trifluoroacetyl, tert-butoxycarbonyl (Boc),benzyloxycarbonyl, and 9-fluorenylmethoxycarbonyl (Fmoc). Suitablehydroxy protecting groups include acetyl and silyl groups such as thetert-butyldimethylsilyl group. For a general description of protectinggroups and their use, see T. W. Greene and P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, John Wiley & Sons, New York, USA, 1991.

Conventional methods and techniques of separation and purification canbe used to isolate compounds of the invention, as well as variousintermediates related thereto. Such techniques may include, for example,all types of chromatography (high performance liquid chromatography(HPLC), column chromatography using common absorbents such as silicagel, and thin layer chromatography), recrystallization, and differential(i.e., liquid-liquid) extraction techniques.

Compounds of the Formula II where R, R′, R₂, n, m, and Z are as definedabove can be prepared starting from 2,4-dichloro-3-nitroquinoline XV asshown in Reaction Scheme I. The route shown in Reaction Scheme I isespecially useful when Z, R′, and R₂ contain functional groups that areeasily oxidized by reagents used in step (4) of Reaction Scheme II.Easily oxidizable groups include —S—, heteroaryl groups, and amines. Instep (1) of Reaction Scheme I, a 2,4-dichloro-3-nitroquinoline ofFormula XV is reacted with an amine of the Formula XVI or hydrochloridesalt thereof to form a compound of Formula XVII. This reaction iscarried out by adding a compound of Formula XVI or a salt thereof to asolution of 2,4-dichloro-3-nitroquinoline of Formula XV in the presenceof a base such as triethylamine. The reaction is carried out in asuitable solvent, such as dichloromethane or chloroform. Amines of theFormula XVI and hydrochloride salts thereof can be obtained commerciallyor prepared according to published procedures or modified versionsthereof, and according to Schemes III-V and XI. Compounds of Formula XVare known or can be prepared using known synthetic methods, see forexample, U.S. Pat. No. 4,988,815 and the documents cited therein.

The resultant compound of Formula XVII is reduced in step (2) ofReaction Scheme I to provide a quinoline-3,4-diamine of Formula XVIII.The reaction can be carried out by hydrogenation using a heterogeneoushydrogenation catalyst such as platinum on carbon or palladium oncarbon. The hydrogenation is conveniently carried out in a Parrapparatus in a suitable solvent such as acetonitrile, ethyl acetate, orethanol. The reaction can be carried out at ambient temperature, and theproduct can be isolated using conventional methods.

Alternatively step (2) can be carried out using a one- or two-phasesodium dithionite reduction. The reaction is conveniently carried outusing the conditions described by K.K. Park et al., W. K.; TetrahedronLett., 34, 7445-7446 (1993) by adding sodium dithionite to a compound ofFormula XVII in a mixture of dichloromethane and water at ambienttemperature in the presence of potassium carbonate and ethyl viologendibromide, ethyl viologen diiodide, or 1,1′-di-n-octyl-4,4′-bipyridiniumdibromide. The product can be isolated using conventional methods.

In step (3) of Reaction Scheme I, a quinoline-3,4-diamine of FormulaXVIII is treated with a carboxylic acid equivalent to provide a1H-imidazo[4,5-c]quinoline of Formula XIX. Suitable carboxylic acidequivalents include orthoesters of Formula R₂C(O-alkyl)₃,1,1-dialkoxyalkyl alkanoates of Formula R₂C(O-alkyl)₂(O—C(O)-alkyl), andacid chlorides of Formula R₂C(O)Cl. The selection of the carboxylic acidequivalent is determined by the desired substituent at R₂. For example,ethoxyacetyl chloride will provide a compound where R₂ is anethoxymethyl group, and acetyl chloride will provide a compound where R₂is a methyl group. Step (3) can be carried out in two steps when an acidchloride of Formula R₂C(O)Cl is used as the carboxylic acid equivalent.The first step is conveniently carried out by adding the acid chlorideto a solution of a quinoline-3,4-diamine of Formula XVIII in a suitablesolvent such as dichloromethane in the presence of a base such astriethylamine, pyridine, or 4-dimethylaminopyridine to afford an amide.Optionally, the reaction can be performed without a tertiary amine. Thereaction can be carried out starting at a sub-ambient temperature, suchas 0° C., with warming to ambient temperature or at ambient temperature.The amide product can be isolated and optionally purified usingconventional techniques before it is heated and cyclized to provide a1H-imidazo[4,5-c]quinoline of Formula XIX. The cyclization reaction isconveniently carried out in a solvent such as ethanol or methanol in thepresence of a base such as triethylamine and may be carried out at anelevated temperature, such as the reflux temperature of the solvent. The1H-imidazo[4,5-c]quinoline of Formula XIX can be isolated usingconventional methods.

Alternatively, step (3) can be carried out in one step when orthoestersof Formula R₂C(O-alkyl)₃ or 1,1-dialkoxyalkyl alkanoates of FormulaR₂C(O-alkyl)₂(O—C(O)-alkyl) are used. For example, triethyl orthoformatewill provide a compound where R₂ is hydrogen, and trimethylorthovalerate will provide a compound where R₂ is a butyl group. Thereaction is conveniently carried out by adding the carboxylic acidequivalent to a quinoline-3,4-diamine of Formula XVIII in a suitablesolvent such as toluene. Optionally, catalytic pyridine hydrochloride orpyridiump-toluenesulfonate can be added. The reaction is carried out atan elevated temperature, such as at reflux.

In step (4) of Reaction Scheme I, a compound of Formula XIX is reactedwith ammonia in a suitable solvent at elevated temperature and pressure.The product of Formula II or a pharmaceutically acceptable salt thereofcan be isolated by conventional methods.

Compounds of Formula IIa can be prepared according to Reaction SchemeII, wherein R, n, and m are as defined above, and Z_(a) and R_(2a) aresubsets of Z and R₂ as defined above that do not include thosesubstitutents that one skilled in the art would recognize as beingsusceptible to the oxidation in step (4) or incompatible with otherfunctional groups present. Those substitutents include —S—, heteroarylgroups, and alkyl amines. One exception is that —S— is included in theset of Z_(a) and is oxidized to a sulfone during step (4). Therefore,Z_(b) is a subset of Z that contains —S(O)₂— and all of Z_(a) except for—S—. In step (1) of Reaction Scheme II, a 4-chloro-3-nitroquinoline ofFormula XX is reacted with an amine of the Formula XVIa or hydrochloridesalt thereof to form a compound of Formula XXI. Amines of the FormulaXVIa and hydrochloride salts thereof can be obtained commercially orprepared according to published procedures or modified versions thereof,and according to Schemes III-V. Many compounds of Formula XX are knownor can be prepared using known synthetic methods, see for example, U.S.Pat. Nos. 4,689,338; 5,175,296; 5,367,076; and 5,389,640; and thedocuments cited therein. Step (1) of Reaction Scheme II is carried outas described for step (1) of Reaction Scheme I, as are steps (2) and(3).

In step (4) of Reaction Scheme II, a 1H-imidazo[4,5-c]quinoline ofFormula XXIII is oxidized to provide a1H-imidazo[4,5-c]quinoline-5N-oxide of Formula XXIV using a conventionaloxidizing agent capable of forming N-oxides. The reaction isconveniently carried out by adding 3-chloroperoxybenzoic acid to asolution of a compound of Formula XXIII in a solvent such asdichloromethane or chloroform. The reaction can be carried out atambient temperature, and the product can be isolated using conventionalmethods.

In step (5) of Reaction Scheme II, a 1H-imidazo[4,5-c]quinoline-5N-oxideof Formula XXIV is aminated to provide a1H-imidazo[4,5-c]quinolin-4-amine of Formula IIa. Step (5) can becarried out by the activation of an N-oxide of Formula XXIV byconversion to an ester and then reacting the ester with an aminatingagent. Suitable activating agents include alkyl- or arylsulfonylchlorides such as benzenesulfonyl chloride, methanesulfonyl chloride, orp-toluenesulfonyl chloride. Suitable aminating agents include ammonia,in the form of ammonium hydroxide, for example, and ammonium salts suchas ammonium carbonate, ammonium bicarbonate, and ammonium phosphate. Thereaction is conveniently carried out by adding ammonium hydroxide to asolution of the N-oxide of Formula XXIV in a suitable solvent such asdichloromethane or chloroform and then adding p-toluenesulfonylchloride. The reaction can be carried out at ambient temperature. Theproduct or pharmaceutically acceptable salt thereof can be isolatedusing conventional methods.

Alternatively step (5) can be carried out by the reaction of a1H-imidazo[4,5-c]quinoline-5N-oxide of Formula XXIV with trichloroacetylisocyanate followed by base-promoted hydrolysis of the resultingintermediate to provide a 1H-imidazo[4,5-c]quinolin-4-amine of FormulaIIa. The reaction is conveniently carried out in two steps by (i) addingtrichloroacetyl isocyanate to a solution of the N-oxide of Formula XXIVin a solvent such as dichloromethane and stirring at ambient temperatureto provide an amide intermediate which may be isolated. In step (ii), asolution of the intermediate in methanol is treated with a base such assodium methoxide or ammonium hydroxide at ambient temperature. Theproduct or a pharmaceutically acceptable salt thereof can be isolatedusing conventional methods.

Steps (4) and (5) of Reaction Scheme II may be carried out as a one-potprocedure by adding 3-chloroperoxybenzoic acid to a solution of acompound of Formula XXIII in a solvent such as dichloromethane orchloroform and then adding ammonium hydroxide and p-toluenesulfonylchloride without isolating the N-oxide compound of Formula XXIV. Theproduct of Formula IIa or pharmaceutically acceptable salt thereof canbe isolated by conventional methods.

The amine of the Formula XVI where m is 1, R′ is —OH, and Z is—CH₂CH₂CH₂— can be obtained commercially as the hydrochloride salt. Someamines of the Formula XVI can be prepared according to publishedprocedures or modified versions thereof. For example, the amine ofFormula XVI where m is 2, R′ is —OH, and Z is —CH₂CH₂CH₂— has beenprepared previously by J. Bicking et al., J. Med. Chem., 26, 342-348(1983). The route described by J. Bicking et al. may also be appliedtoward the synthesis of many amines of Formula XVI where m is 2 and R′is —OH. In a publication by I. L. Lysenko et al., Russ. J. Org. Chem.,37, 1238-1243 (2001), the synthesis of the amine of Formula XVI where mis 1, R′ is —OH, and Z is a bond has been described. The synthesis ofthe amine of Formula XVI where m is 3, R′ is —OH, and Z is a bond frombutyrolactone has been published by A. Esposito et al., J. Org. Chem.,65, 9245-9248 (2000). The method described by A. Esposito et al. may beapplied toward the synthesis of amines of Formula XVI where m is 2, 4,and 5, R′ is —OH, and Z is a bond starting from the appropriatecommercially available lactones. Other amines of Formula XVI where R′ is—OH may be prepared according to Schemes III-V.

Amines of the Formula XVIb where Z is defined as above and hydrochloridesalts thereof can be prepared according to Reaction Scheme III. In step(1) of Reaction Scheme III, a ketone of Formula XXV can be treated withexcess nitromethane in a suitable solvent such as ethanol or methanol inthe presence of a catalytic amount of base such as sodium ethoxide orsodium hydroxide to provide a compound of Formula XXVI. A wide varietyof ketones of Formula XXV can be obtained from commercial sources or canbe synthesized using known synthetic methods. The reaction can becarried out at ambient temperature. The product of Formula XXVI can beisolated using conventional methods.

Step (2) of Reaction Scheme III can be carried out by hydrogenationusing a heterogeneous hydrogenation catalyst such as palladium hydroxideon carbon or palladium on carbon or Raney nickel. The hydrogenation isconveniently carried out in a Parr apparatus in a suitable solvent suchas ethanol or methanol. The reaction can be carried out at ambienttemperature, and the product amino alcohol of Formula XVIb can beisolated using conventional methods.

Alternatively, amino alcohols of Formula XVIb can be prepared bytreating a ketone of Formula XXV with a cyanide source, such astrimethylsilylcyanide, in the presence of a catalytic amount of a crownether, such as 18-crown-6, and a catalytic amount of a cyanide source,such as potassium cyanide. The intermediate cyanohydrin is then reducedwith a hydride reducing agent, such as lithium aluminum hydride. Thereduction may be carried out at a sub-ambient temperature, such as 0°C., in a suitable solvent such as THF, and the amino alcohol of FormulaXVIb can be isolated by conventional methods.

Reaction Scheme IV shows the synthesis of amines of Formula XVIc wherem′ may equal 0-3, Z is defined as above, and TBS- is atert-butyldimethylsilyl group. In step (1), a ketone of Formula XXV istreated with an organometallic reagent of the Formula H₂C═CH₂(CH₂)_(m′)Mwhere M is MgCl, MgBr, MgI, ZnBr, ZnI, or Li, or the product of suchreagent with CeCl₃. The organometallic reagents are commerciallyavailable or can be prepared from H₂C═CH₂(CH₂)_(m′)X, where X is achloride or preferably a bromide or iodide. The reaction can be carriedout in an appropriate solvent such as tetrahydrofuran or diethyl ether.The resulting tertiary alcohol of Formula XXVII can be isolated usingconventional methods.

In step (2) of Reaction Scheme IV, the newly formed tertiary alcohol ofFormula XXVII is protected as a tert-butyldimethylsilyl (TBS) ether toyield the product of Formula XXVIII. The tertiary alcohol of FormulaXXVII can be reacted with tert-butyldimethylsilyl chloride ortert-butyldimethylsilyl triflate with a base such as pyridine,2,6-lutidine, triethylamine, or ethyldiisopropylamine in an appropriatesolvent such as acetonitrile or dichloromethane optionally with acatalytic amount of dimethylaminopyridine. The resulting compound ofFormula XXVIII can be isolated using conventional methods.

In step (3) of Reaction Scheme IV, the terminal olefin of Formula XXVIIIundergoes hydroboration and subsequent oxidation to provide a primaryalcohol of Formula XXIX. The two step procedure is carried out by firstadding a reagent such as borane, catecholborane or9-borabicyclo(3.3.1)nonane with or without (PPh₃)₃RhCl present in anappropriate solvent such as tetrahydrofuran to generate an alkyl boraneintermediate. Sodium hydroxide and an aqueous solution of hydrogenperoxide are added to convert the intermediate to the product of FormulaXXIX, which can be isolated using conventional methods.

In step (4) of Reaction Scheme IV, the primary alcohol of Formula XXIXis reacted with methanesulfonyl chloride to yield a compound of FormulaXXX. The reaction is conveniently carried out in a solvent such asdichloromethane in the presence of a base such as triethylamine. Thereaction may be carried out starting at a sub-ambient temperature, suchas 0° C., with warming to ambient temperature. The resulting compound ofFormula XXX can be isolated using conventional methods.

In step (5) of Reaction Scheme IV, the compound of Formula XXX may bereacted with sodium azide in a suitable solvent such asdimethylformamide. The reaction may be carried out at ambienttemperature or at elevated temperature. The resulting compound ofFormula XXXI can be isolated using conventional methods.

In step (6) of Reaction Scheme IV, the tert-butyldimethylsilyl (TBS)group is removed from the compound of Formula XXXI to generate thealcohol in a compound of Formula XXXII. Typically, a compound of FormulaXXXI is treated with a fluoride source such as tetrabutylammoniumfluoride in a suitable solvent such as tetrahydrofuran with or withoutacetic acid added. Alternatively, hydrogen fluoride-pyridine may be usedin a suitable solvent such as tetrahydrofuran optionally with pyridineadded to the reaction. The reaction can be carried out at ambienttemperature. The resulting compound of Formula XXXII can be isolatedusing conventional methods.

In step (7) of Reaction Scheme IV, a compound of Formula XXXII can bereduced to provide a amino alcohol of Formula XVIc. The reaction can becarried out by hydrogenation using a heterogeneous hydrogenationcatalyst such as palladium on carbon. The hydrogenation is convenientlycarried out in a Parr apparatus in a suitable solvent such as ethanol.The reaction can be carried out at ambient temperature, and the productof Formula XVIc where R′_(a) is —OH can be isolated using conventionalmethods.

In step (7a) of Reaction Scheme IV, an azide of Formula XXXI may bereduced using the conditions described in step (7) of Reaction Scheme IVto yield the corresponding amine of Formula XVIc where R′_(a) is —OTBS,which may be used in place of an amine of Formula XVIa in ReactionScheme II. Subsequent removal of the tert-butyldimethylsilyl protectinggroup after completion of step (4) of Reaction Scheme II using aqueoushydrogen chloride in a suitable solvent such as methanol or using theconditions described for step (6) in Reaction Scheme IV ultimatelyprovides a compound of Formula XXIII, which can be converted to acompound of Formula IIa.

Reaction Scheme V shows a general synthesis of amines of Formula XVIdwhere m equals 1-5 and Bz is a benzyl group. Compounds of the FormulaXXXIII are used as the starting material and can be obtained fromcommercial sources or can be readily synthesized as described by R. K.Olsen et al., J. Org. Chem., 47, 4605-4611 (1982), S. Kobayashi et al.,Syn. Lett., 909-912 (1999), and C. F. Garcia et al., J. Chem. Soc. Chem.Commun., 12, 1465-1466 (1996). In step (1) of Reaction Scheme V, acyclopropane of Formula XXXIV is formed upon treatment of the startingmaterial of Formula XXXIII with ethylmagnesium bromide in the presenceof titanium(IV) isopropoxide in a suitable solvent such astetrahydrofuran at sub-ambient temperature. The product of Formula XXXIVcan be isolated using conventional methods.

In step (2) of reaction Scheme V, a compound of Formula XVId is preparedby the reduction of compound of Formula XXXIV. The reaction can becarried out by hydrogenation using a heterogeneous hydrogenationcatalyst such as palladium on carbon. The hydrogenation is convenientlycarried out in a Parr apparatus using a suitable solvent such asethanol, methanol, or ethyl acetate. The reaction can be performed atambient temperature, and the product of Formula XVId can be isolatedusing conventional methods.

Functional group transformations in a compound of Formula XXIII arepossible using known synthetic methods. For example, as shown in step(1) of Reaction Scheme VI, a compound of Formula XXIII whereZ_(a)=—(CH₂)₀₋₃—NBoc-(CH₂)₀₋₃— (Boc is defined as tert-butyloxycarbonyl)can be treated with acid to remove the Boc group to yield an amine ofFormula XXXV. In step (2) of Reaction Scheme VI, an amine of FormulaXXXV can react with an acid chloride of Formula R₄C(O)Cl, an alkylchloroformate of Formula R₄OC(O)Cl, a sulfonyl chloride of FormulaR₄S(O)₂Cl, a sulfonic anydride of Formula (R₄S(O)₂)₂O, or an acidanhydride of the Formula (R₄C(O))₂O to provide compound of Formula XXIIIin which Z_(a) is —CH₂-A′-CH₂— and A′ is —N(Q-R₄) where R₄ is defined asabove and Q is —C(O)—, —C(O)O—, —S(O)₂—. Numerous acid chlorides, alkylchloroformates, sulfonyl chlorides, and sulfonic anhydrides arecommercially available; others can be prepared readily using knownsynthetic methods. The reaction can be conveniently carried out byadding the acid chloride, alkyl chloroformate, sulfonyl chloride,sulfonic anhydride, or acid anhydride to a solution of amine of FormulaXXXV in a suitable solvent such as pyridine. The reaction can be carriedout at ambient temperature and the product can be isolated usingconventional methods. In step (3) of Reaction Scheme VI, the tertiaryhydroxy group of a 1H-imidazo[4,5-c]quinoline of Formula XXIII can bealkylated to produce an ether of Formula XXXVI. The reaction isconveniently carried out in a suitable solvent such as tetrahydrofuranusing a base such as sodium hydride or potassium hydride to firstdeprotonate the alcohol, followed by addition of an alkyl iodide oralkyl triflate. The reaction can be carried out at elevated temperature.Alternatively, the hydroxy group can be reacted with methyl vinylsulfone after treatment with a sub-stoichiometric amount of sodiumhydride in a suitable solvent such as tetrahydrofuran at ambienttemperature. The product of Formula XXXVI can be isolated usingconventional methods. Steps (4) and (5) can be carried out as describedfor steps (4) and (5) of Reaction Scheme II to provide a compound ofFormula IIb.

For some embodiments, compounds shown in Reaction Schemes I and II canbe further elaborated using conventional synthetic methods. For example,as shown in Scheme VII, a compound of Formula IIa, where Z is—(CH₂)₀₋₃—NBoc-(CH₂)₀₋₃— and Boc is defined as tert-butyloxycarbonyl,can undergo acid mediated cleavage of the Boc group in step (1) to givea secondary amine that can be functionalized in step (2) with an acidchloride of Formula R₄C(O)Cl, an alkyl chloroformate of FormulaR₄OC(O)Cl, a sulfonyl chloride of Formula R₄S(O)₂Cl, a sulfonic anydrideof Formula (R₄S(O)₂)₂O, an isocyanate of formula R₄NCO, or anisothiocyanate of formula R₄NCS to provide a compound of Formula IId inwhich Z is —(CH₂)₀₋₃-A′-(CH₂)₀₋₃— and A′ is —N(Q-R₄) where R₄ is definedas above and Q is —C(O)—, —C(O)O—, —S(O)₂—, —C(O)NH—, or —C(S)NH—.Alternatively, a compound of Formula XXIII in Reaction Scheme II, whereZ_(a)=—(CH₂)₀₋₃—NBoc-(CH₂)₀₋₃— for example, can be treated with acid toremove the Boc group. The resulting amine can react further with an acidchloride of Formula R₄C(O)Cl, an alkyl chloroformate of FormulaR₄OC(O)Cl, a sulfonyl chloride of Formula R₄S(O)₂Cl, a sulfonic anydrideof Formula (R₄S(O)₂)₂O, or an isocyanate of formula R₄NCO before step(4) of Reaction Scheme II. The product can then be treated according tosteps (4) and (5) of Reaction Scheme II to provide compound of FormulaIId in which Z is —(CH₂)₀₋₃-A′-(CH₂)₀₋₃— and A′ is —N(Q-R₄) where R₄ isdefined as above and Q is —C(O)—, —C(O)O—, —S(O)₂—, or —C(O)NH—.Numerous acid chlorides, alkyl chloroformates, sulfonyl chlorides,sulfonic anhydrides, isocyanates, and isothiocyanates are commerciallyavailable; others can be prepared readily using known synthetic methods.The reaction can be conveniently carried out by adding the acidchloride, alkyl chloroformate, sulfonyl chloride, sulfonic anhydride,isocyanate, or isothiocyanate to a solution of amine of Formula IIc orXXIII, in which Z or Z_(a) contains a secondary amine in a suitablesolvent such as pyridine. The reaction can be carried out at ambienttemperature.

In addition, a compound of Formula IIc in Reaction Scheme VII canundergo alkylation of the secondary amine. In step (3) the compound ofFormula IIc may react with aldehydes, alkyl halides or triflates toprovide a compound Formula IIe in which R₈ is defined as above. Forexample, treatment of a compound of Formula IIc with aqueousformaldehyde and a reducing agent such as sodium cyanoborohydride in anappropriate solvent such as methanol yields a compound of Formula IIe,where R₈ is a methyl group.

Compounds of the invention of Formula IIf and IIg can be preparedaccording to Reaction Scheme VIII, wherein R, n, Z_(a), Z_(b), andR_(2a) are defined as above. In step (1) of Reaction Scheme VIII, a4-chloro-3-nitroquinoline of Formula XX is reacted with an amine of theFormula XVIe or a salt thereof to form a compound of Formula XXXVIII.This reaction is carried out as described for step (1) in ReactionScheme I. Amines of the Formula XVIe and salts thereof can be preparedaccording to published procedures or modified versions thereof, or byusing conventional synthetic methods. For example, the synthesis ofamines of the Formula XVI where m is one, R′═NH₂ and Z is —(CH₂)₂₋₄—,and —CH₂(NCH₃)CH₂— has been published by M. A. Fernandez et al., Analesde la Real Academia de Farmacia, 54, 502-510 (1988). The startingmaterials used by M. A. Fernandez et al. were ketones of Formula XXV. Awide variety of ketones of Formula XXV can be obtained from commercialsources or can be synthesized. Those ketones of Formula XXV may be usedin the synthesis of amines of Formula XVI where m is one, R′═NH₂ and Zis as described above. Similar chemistry to that published by Fernandezet al. that is also relevant has been published by S. L. Deng et al.,Synthesis, 2445-2449 (2001), A. A. Cordi et al., J. Med. Chem., 44,787-805 (2001), and M. Freifelder et al., J. Amer. Chem. Soc., 82,696-698 (1960). In addition, the amine of Formula XVIe wherein m is oneand Z_(a) is a bond has been synthesized previously by F. Vergne et al.,J. Org. Chem., 57, 6071-6075 (1992). Many compounds of Formula XX areknown or can be prepared using known synthetic methods, see for example,U.S. Pat. Nos. 4,689,338; 5,175,296; 5,367,076; and 5,389,640; and thedocuments cited therein.

In step (2) of Reaction Scheme VIII, the primary amine in a compound ofFormula XXXVIII is converted into a tert-butyl carbamate to provide acompound of Formula XXXIX. The reaction is conveniently carried outusing di-tert-butyldicarbonate in the presence of a base such as aqueoussodium hydroxide in a solvent such as tetrahydrofuran. The compound ofFormula XXXIX can be isolated using conventional methods.

Steps (3), (4), (5), and (6) of Reaction Scheme VIII can be carried outas described for steps (2), (3), (4), and (5), respectively, of ReactionScheme II to provide a compound of Formula IIf.

In step (7) of Reaction Scheme VIII, the tert-butyl carbamate in acompound of Formula IIf is converted to a primary amine of Formula IIg.The reaction is conveniently performed in the presence of an acid suchas hydrogen chloride in a suitable solvent such as ethanol. The reactionis performed at elevated temperature and the product of Formula IIg or apharmaceutically acceptable salt thereof is isolated using conventionalmethods.

For some embodiments, compounds shown in Reaction Scheme VIII can befurther elaborated using conventional synthetic methods. For example, asshown in Scheme IX, a compound of Formula XLI can undergo acid mediatedcleavage of the Boc group in step (1) to give a primary amine of FormulaXLIII that can be functionalized with the reagents described in step (2)of Reaction Scheme VII to provide a compound of Formula XLIV in whichwhere R₄ is defined as above and Q is —C(O)—, —C(O)O—, —S(O)₂—,—C(O)NH—, or —C(S)NH—. The reaction can be carried out in an appropriatesolvent such as dichloromethane in the presence of a tertiary amine suchas triethylamine, or can be performed in pyridine. Optionally,dimethylaminopyridine may be used in the reaction. The reaction iscarried out at ambient temperature. Steps (3) and (4) of Reaction SchemeIX can be carried out as described for steps (4) and (5) in ReactionScheme II to yield a compound of Formula IIh. If Z_(b) in a compound ofFormula IIh contains an appropriately protected amine, deprotection willprovide a free amine that may be functionalized with the reagentsdescribed in step (2) of Reaction Scheme VII.

Compounds of the Formula IIi can be prepared according to ReactionScheme X, wherein R, n, and m are as defined above, and Z_(a), Z_(b) andR_(2a) are subsets of Z and R₂ as defined above. In step (1) of ReactionScheme X, 4-chloro-3-nitroquinoline of Formula XX is reacted with anamine of the Formula XVIf or hydrochloride salt thereof to form acompound of Formula XLV. Step (1) of Reaction Scheme X is carried out asdescribed for step (1) in Reaction Scheme II. Steps (2), (3), (4), and(5) of Reaction Scheme X can be carried out as described for steps (2),(3), (4), and (5), respectively, of Reaction Scheme II to provide acompound of Formula IIi or a pharmaceutically active salt thereof

Some amines of the Formula XVIf and hydrochloride salts thereof can beprepared according to Reaction Scheme XI and by conventional syntheticmethods. In step (1) of Reaction Scheme XI, a ketone of Formula XXV istreated nitromethane and an alkyl thiol in the presence of a base in anappropriate solvent by modifying the procedure of W. W. Lin et al., J.Org. Chem., 66, 1984-1991 (2001) to yield a compound of Formula XLIX.

In step (2) of Reaction Scheme XI, a compound of Formula XLIX is reducedusing lithium aluminum hydride or hydrogenated using a heterogeneoushydrogenation catalyst palladium on carbon. The product of Formula XVIfor salt thereof can be isolated using conventional methods.

Compounds of Formula II where R′ is a sulfide and R, R₂, n, m, and Z areas defined above can be prepared according to the route shown inReaction Scheme I using an amine of Formula XVIf as the startingmaterial.

As shown in Reaction Scheme XII, an 1H-imidazo[4,5-c]quinoline ofFormula IIj can be reduced to a6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine of Formula Ma whereZ and R′ are as defined above and R_(2b) and R_(b) are subsets of R₂ andR as defined above that do not include substituents that one skilled inthe art would recognize as being susceptible to reduction under theacidic hydrogenation conditions of step (1). Those susceptible groupsinclude, for example, alkenyl, alkynyl, aryl groups, and groups bearingnitro substituents. The reaction is conveniently carried out underheterogeneous hydrogenation conditions by adding platinum (IV) oxide toa solution of the compound of Formula IIj in trifluoroacetic acid andplacing the reaction under hydrogen pressure. The reaction can becarried out on a Parr apparatus at ambient temperature. The product orpharmaceutically acceptable salt thereof can be isolated by conventionalmethods.

For some embodiments, compounds of the invention are prepared accordingto Reaction Scheme XIII, where Z, R′, R₂, R_(A), and R_(B) are asdefined above. In step (1) of Reaction Scheme XIII, a2,4-dichloro-3-nitropyridine of Formula LI is reacted with an amine ofFormula XVI or a hydrochloride salt thereof to form a2-chloro-3-nitropyridine of Formula LII. The reaction is convenientlycarried out by combining an amine of Formula XVI or a hydrochloride saltthereof and 2,4-dichloro-3-nitropyridine of Formula LI in the presenceof a base such as triethylamine in a solvent such asN,N-dimethylformamide (DMF). The reaction can be carried out at ambienttemperature or above, and the product can be isolated from the reactionmixture using conventional methods. Many 2,4-dichloro-3-nitropyridinesof Formula LI are known and can be readily prepared using knownsynthetic methods. (See, for example, U.S. Pat. No. 6,525,064 (Dellariaet al.) and the references cited therein.)

In step (2) of Reaction Scheme XIII, a 2-chloro-3-nitropyridine ofFormula LII is reacted with dibenzylamine to provide a compound ofFormula LIII. The reaction can be carried out by combining the compoundof Formula LII with dibenzylamine and a tertiary amine such astriethylamine in a suitable solvent such as toluene. The reaction can becarried out at elevated temperature and the product of Formula LIII isisolated from the reaction mixture using conventional methods.

In step (3) of Reaction Scheme XIII, a compound of formula LIII isreduced to provide a compound of Formula LIV. The reduction can becarried out by hydrogenation using a conventional heterogeneouscatalyst, for example, platinum on carbon or palladium on carbon. Thereaction can conveniently be carried out on a Parr apparatus in asuitable solvent such as acetonitrile or ethyl acetate. The product ofFormula LIV can be isolated from the reaction mixture using conventionalmethods.

In step (4) of reaction Scheme XIII, a compound of Formula LIV isreacted with a carboxylic acid equivalent to provide a compound ofFormula LV. The reaction can be carried out as described in step (3) ofReaction Scheme I, and the product can be isolated from the reactionmixture using conventional methods.

A compound of Formula LV may also be prepared by subjecting a compoundof Formula LII to the reaction conditions in described in steps (3) and(4) to provide a 4-chloroimidazopyridine which may then be treated withdibenzylamine in a microwave to provide a compound of Formula LV.

In step (5) of reaction Scheme XIII, the benzyl groups of a compound ofFormula LV are cleaved to provide a compound of Formula III. Thereaction can be carried out by transfer hydrogenation in the presence ofa suitable hydrogenation catalyst. The transfer hydrogenation isconveniently carried out by adding ammonium formate to a solution of acompound of Formula LV in a suitable solvent such as ethanol or methanolin the presence of a catalyst such as palladium on carbon. The reactionis carried out at an elevated temperature, for example, the refluxtemperature of the solvent. The product of Formula III orpharmaceutically acceptable salt thereof can be isolated usingconventional methods.

Compounds of the invention can be prepared according to Reaction SchemeXIV, wherein R, Z_(a), Z_(b), R_(2a) and m are as defined above.Reaction Scheme XIV begins with a 4-chloro-3-nitro[1,5]naphthyridine ofFormula LVI. Compounds of Formula LVI and their preparation are known;see, for example, U.S. Pat. No. 6,194,425 (Gerster) and U.S. Pat. No.6,518,280 (Gerster). Steps (1) through (5) of Reaction Scheme XIV can becarried out as described for the corresponding steps (1) through (5) ofReaction Scheme II to provide a substituted1H-imidazo[4,5-c]-1,5-naphthyridin-4-amine of Formula IVa. The productor pharmaceutically acceptable salt thereof can be isolated byconventional methods.

For some embodiments, naphthyridines of the invention are prepared fromtetrazolo compounds of Formulas LVIII and LXI according to ReactionScheme XV, wherein R, R′, R₂, m, and Z are as defined above and -OTf isa trifluoromethanesulfonate group. Compounds of Formula LVIII and LXIand synthetic routes to these compounds are known; see, for example,U.S. Pat. No. 6,194,425 (Gerster) and U.S. Pat. No. 6,518,280 (Gerster).

In steps (1) and (1a) of Reaction Scheme XV, a tetrazolonaphthyridine ofFormula LVIII or LXI is reacted with an amine of Formula XVI or ahydrochloride salt thereof to form a compound of Formula LIX or LXII.The reaction can be carried out as described in step (1) of ReactionScheme I. A compound of Formula LIX or LXII is converted to a compoundof Formula LX or LXIII according to the methods of steps (2) and (3) ofReaction Scheme I. The tetrazolo group of a compound of Formula LX orLXIII can then be removed to provide a1H-imidazo[4,5-c]naphthyridin-4-amine of Formula VII or VIII. Theremoval of the tetrazolo group can be carried out by methods describedin U.S. Pat. No. 6,194,425 (Gerster) and U.S. Pat. No. 6,518,280(Gerster). The product or pharmaceutically acceptable salt thereof canbe isolated by conventional methods.

Compounds of the invention can also be prepared using variations of thesynthetic routes shown in Reaction Schemes I through XV. For example,tetrahydronapthyridines can be prepared using the method described inReaction Scheme XII for the preparation of tetrahydroquinolines.Compounds of the invention can also be prepared using the syntheticroutes described in the EXAMPLES below.

Prodrugs can be prepared in a variety of ways. For example, a compoundwherein R₂ is —X—OH can be converted into a prodrug wherein R₂ is, forexample, —X—O—C(R₆)—R₄, —X—O—C(R₆)—O—R₄, or —X—O—C(R₆)—N(R₈)—R₄, whereinR₄, R₆, and R₈ are as defined above, using methods known to one skilledin the art. In addition, a compound wherein R′ or R is hydroxy may alsobe converted to an ester, an ether, a carbonate, or a carbamate. For anyof these compounds containing an alcohol functional group, a prodrug canbe formed by the replacement of the hydrogen atom of the alcohol groupwith a group such as C₁₋₆ alkanoyloxymethyl, 1-(C₁₋₆ alkanoyloxy)ethyl,1-methyl-1-(C₁₋₆ alkanoyloxy)ethyl, C₁₋₆ alkoxycarbonyloxymethyl,N—(C₁₋₆ alkoxycarbonyl)aminomethyl, succinoyl, C₁₋₆ alkanoyl,α-aminoC₁₋₄ alkanoyl, arylacyl, —P(O)(OH)₂, —P(O)(O—C₁₋₆ alkyl)₂, C₁₋₆alkoxycarbonyl, C₁₋₆ alkylcarbamoyl, and α-aminoacyl orα-aminoacyl-α-aminoacyl, where each α-aminoacyl group is independentlyselected from racemic, D-, and L-amino acids. For compounds containingan alcohol functional group, particularly useful prodrugs are estersmade from carboxylic acids containing one to six carbon atoms,unsubstituted or substituted benzoic acid esters, or esters made fromracemic, D-, or L-amino acids.

Prodrugs can also be made from a compound containing an amino group byconversion of the amino group to a functional group such as an amide,carbamate, urea, amidine, or another hydrolysable group usingconventional methods. A prodrug of this type can be made by thereplacement of a hydrogen atom in an amino group, particularly the aminogroup at the 4-position, with a group such as —C(O)—R″, α-aminoacyl,α-aminoacyl-α-aminoacyl, —C(O)—O—R″, —C(O)—N(R′″)—R″, —C(═NY′)—R″,—CH(OH)—C(O)—OY′, —CH(OC₁₋₄ alkyl)Y₀, —CH₂Y₁, or —CH(CH₃)Y₁; wherein R″and R′″ are each independently C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, or benzyl,each of which may be unsubstituted or substituted by one or moresubstituents selected from the group consisting of halogen, hydroxy,nitro, cyano, carboxy, C₁₋₆ alkyl, C₁₋₄ alkoxy, aryl, heteroaryl,arylC₁₋₄ alkylenyl, heteroarylC₁₋₄ alkylenyl, haloC₁₋₄ alkylenyl,haloC₁₋₄ alkoxy, —O—C(O)—CH₃, —C(O)—O—CH₃, —C(O)—NH₂, —O—CH₂—C(O)—NH₂,—NH₂, and —S(O)₂—NH₂, with the proviso that R′″ can also be hydrogen;each α-aminoacyl group is independently selected from racemic, D-, andL-amino acids; Y′ is hydrogen, C₁₋₆ alkyl, or benzyl; Y₀ is C₁₋₆ alkyl,carboxyC₁₋₆ alkylenyl, aminoC₁₋₄ alkylenyl, mono-N—C₁₋₆ alkylaminoC₁₋₄alkylenyl, or di-N,N—C₁₋₆ alkylaminoC₁₋₄ alkylenyl; and Y₁ ismono-N—C₁₋₆ alkylamino, di-N,N—C₁₋₆ alkylamino, morpholin-4-yl,piperidin-1-yl, pyrrolidin-1-yl, or 4-C₁₋₄ alkylpiperazin-1-yl.

Pharmaceutical Compositions and Biological Activity

Pharmaceutical compositions of the invention contain a therapeuticallyeffective amount of a compound or salt of the invention as describedabove in combination with a pharmaceutically acceptable carrier.

The terms “a therapeutically effective amount” and “effective amount”mean an amount of the compound or salt sufficient to induce atherapeutic or prophylactic effect, such as cytokine induction,immunomodulation, antitumor activity, and/or antiviral activity.Although the exact amount of active compound or salt used in apharmaceutical composition of the invention will vary according tofactors known to those of skill in the art, such as the physical andchemical nature of the compound or salt, the nature of the carrier, andthe intended dosing regimen, it is anticipated that the compositions ofthe invention will contain sufficient active ingredient to provide adose of about 100 nanograms per kilogram (ng/kg) to about 50 milligramsper kilogram (mg/kg), preferably about 10 micrograms per kilogram(μg/kg) to about 5 mg/kg, of the compound or salt to the subject. Avariety of dosage forms may be used, such as tablets, lozenges,capsules, parenteral formulations, syrups, creams, ointments, aerosolformulations, transdermal patches, transmucosal patches and the like.

The compounds or salts of the invention can be administered as thesingle therapeutic agent in the treatment regimen, or the compounds orsalts of the invention may be administered in combination with oneanother or with other active agents, including additional immuneresponse modifiers, antivirals, antibiotics, antibodies, proteins,peptides, oligonucleotides, etc.

Compounds or salts of the invention have been shown to induce theproduction of certain cytokines in experiments performed according tothe test set forth below. These results indicate that the compounds orsalts are useful as immune response modifiers that can modulate theimmune response in a number of different ways, rendering them useful inthe treatment of a variety of disorders.

Cytokines whose production may be induced by the administration ofcompounds or salts of the invention generally include interferon-α(IFN-α) and/or tumor necrosis factor-α (TNF-α) as well as certaininterleukins (IL). Cytokines whose biosynthesis may be induced bycompounds or salts of the invention include IFN-α, TNF-α, IL-1, IL-6,IL-10 and IL-12, and a variety of other cytokines Among other effects,these and other cytokines can inhibit virus production and tumor cellgrowth, making the compounds or salts useful in the treatment of viraldiseases and neoplastic diseases. Accordingly, the invention provides amethod of inducing cytokine biosynthesis in an animal comprisingadministering an effective amount of a compound or salt or compositionof the invention to the animal. The animal to which the compound or saltor composition is administered for induction of cytokine biosynthesismay have a disease as described infra, for example a viral disease or aneoplastic disease, and administration of the compound or salt mayprovide therapeutic treatment. Alternatively, the compound or salt maybe administered to the animal prior to the animal acquiring the diseaseso that administration of the compound or salt may provide aprophylactic treatment.

In addition to the ability to induce the production of cytokines,compounds or salts of the invention can affect other aspects of theinnate immune response. For example, natural killer cell activity may bestimulated, an effect that may be due to cytokine induction. Thecompounds or salts may also activate macrophages, which in turnstimulate secretion of nitric oxide and the production of additionalcytokines. Further, the compounds or salts may cause proliferation anddifferentiation of B-lymphocytes.

Compounds or salts of the invention can also have an effect on theacquired immune response. For example, the production of the T helpertype 1 (T_(H)1) cytokine IFN-γ may be induced indirectly and theproduction of the T helper type 2 (T_(H)2) cytokines IL-4, IL-5 andIL-13 may be inhibited upon administration of the compounds or salts.

Whether for prophylaxis or therapeutic treatment of a disease, andwhether for effecting innate or acquired immunity, the compound or saltor composition may be administered alone or in combination with one ormore active components as in, for example, a vaccine adjuvant. Whenadministered with other components, the compound or salt and othercomponent or components may be administered separately; together butindependently such as in a solution; or together and associated with oneanother such as (a) covalently linked or (b) non-covalently associated,e.g., in a colloidal suspension.

Conditions for which compounds or salts identified herein may be used astreatments include, but are not limited to:

(a) viral diseases such as, for example, diseases resulting frominfection by an adenovirus, a herpesvirus (e.g., HSV-I, HSV-II, CMV, orVZV), a poxvirus (e.g., an orthopoxvirus such as variola or vaccinia, ormolluscum contagiosum), a picornavirus (e.g., rhinovirus orenterovirus), an orthomyxovirus (e.g., influenzavirus), a paramyxovirus(e.g., parainfluenzavirus, mumps virus, measles virus, and respiratorysyncytial virus (RSV)), a coronavirus (e.g., SARS), a papovavirus (e.g.,papillomaviruses, such as those that cause genital warts, common warts,or plantar warts), a hepadnavirus (e.g., hepatitis B virus), aflavivirus (e.g., hepatitis C virus or Dengue virus), or a retrovirus(e.g., a lentivirus such as HIV);

(b) bacterial diseases such as, for example, diseases resulting frominfection by bacteria of, for example, the genus Escherichia,Enterobacter, Salmonella, Staphylococcus, Shigella, Listeria,Aerobacter, Helicobacter, Klebsiella, Proteus, Pseudomonas,Streptococcus, Chlamydia, Mycoplasma, Pneumococcus, Neisseria,Clostridium, Bacillus, Corynebacterium, Mycobacterium, Campylobacter,Vibrio, Serratia, Providencia, Chromobacterium, Brucella, Yersinia,Haemophilus, or Bordetella;

(c) other infectious diseases, such chlamydia, fungal diseases includingbut not limited to candidiasis, aspergillosis, histoplasmosis,cryptococcal meningitis, or parasitic diseases including but not limitedto malaria, pneumocystis carnii pneumonia, leishmaniasis,cryptosporidiosis, toxoplasmosis, and trypanosome infection;

(d) neoplastic diseases, such as intraepithelial neoplasias, cervicaldysplasia, actinic keratosis, basal cell carcinoma, squamous cellcarcinoma, renal cell carcinoma, Kaposi's sarcoma, melanoma, leukemiasincluding but not limited to myelogeous leukemia, chronic lymphocyticleukemia, multiple myeloma, non-Hodgkin's lymphoma, cutaneous T-celllymphoma, B-cell lymphoma, and hairy cell leukemia, and other cancers;

(e) T_(H)2-mediated, atopic diseases, such as atopic dermatitis oreczema, eosinophilia, asthma, allergy, allergic rhinitis, and Ommen'ssyndrome;

(f) certain autoimmune diseases such as systemic lupus erythematosus,essential thrombocythaemia, multiple sclerosis, discoid lupus, alopeciaareata; and

(g) diseases associated with wound repair such as, for example,inhibition of keloid formation and other types of scarring (e.g.,enhancing wound healing, including chronic wounds).

Additionally, a compound or salt of the present invention may be usefulas a vaccine adjuvant for use in conjunction with any material thatraises either humoral and/or cell mediated immune response, such as, forexample, live viral, bacterial, or parasitic immunogens; inactivatedviral, tumor-derived, protozoal, organism-derived, fungal, or bacterialimmunogens; toxoids; toxins; self-antigens; polysaccharides; proteins;glycoproteins; peptides; cellular vaccines; DNA vaccines; autologousvaccines; recombinant proteins; and the like, for use in connectionwith, for example, BCG, cholera, plague, typhoid, hepatitis A, hepatitisB, hepatitis C, influenza A, influenza B, parainfluenza, polio, rabies,measles, mumps, rubella, yellow fever, tetanus, diphtheria, hemophilusinfluenza b, tuberculosis, meningococcal and pneumococcal vaccines,adenovirus, HIV, chicken pox, cytomegalovirus, dengue, feline leukemia,fowl plague, HSV-1 and HSV-2, hog cholera, Japanese encephalitis,respiratory syncytial virus, rotavirus, papilloma virus, yellow fever,and Alzheimer's Disease.

Compounds or salts of the present invention may be particularly helpfulin individuals having compromised immune function. For example,compounds or salts may be used for treating the opportunistic infectionsand tumors that occur after suppression of cell mediated immunity in,for example, transplant patients, cancer patients and HIV patients.

Thus, one or more of the above diseases or types of diseases, forexample, a viral disease or a neoplastic disease may be treated in ananimal in need thereof (having the disease) by administering atherapeutically effective amount of a compound or salt of the inventionto the animal.

An amount of a compound or salt effective to induce cytokinebiosynthesis is an amount sufficient to cause one or more cell types,such as monocytes, macrophages, dendritic cells and B-cells to producean amount of one or more cytokines such as, for example, IFN-α, TNF-α,IL-1, IL-6, IL-10 and IL-12 that is increased (induced) over abackground level of such cytokines. The precise amount will varyaccording to factors known in the art but is expected to be a dose ofabout 100 ng/kg to about 50 mg/kg, preferably about 10 μg/kg to about 5mg/kg. The invention also provides a method of treating a viralinfection in an animal and a method of treating a neoplastic disease inan animal comprising administering an effective amount of a compound orsalt or composition of the invention to the animal. An amount effectiveto treat or inhibit a viral infection is an amount that will cause areduction in one or more of the manifestations of viral infection, suchas viral lesions, viral load, rate of virus production, and mortality ascompared to untreated control animals. The precise amount that iseffective for such treatment will vary according to factors known in theart but is expected to be a dose of about 100 ng/kg to about 50 mg/kg,preferably about 10 μg/kg to about 5 mg/kg. An amount of a compound orsalt effective to treat a neoplastic condition is an amount that willcause a reduction in tumor size or in the number of tumor foci. Again,the precise amount will vary according to factors known in the art butis expected to be a dose of about 100 ng/kg to about 50 mg/kg,preferably about 10 μg/kg to about 5 mg/kg.

In addition to the formulations and uses described specifically herein,other formulations, uses, and administration devices suitable forcompounds of the present invention are described in, for example,International Publication Nos. WO 03/077944 and WO 02/036592, U.S. Pat.No. 6,245,776, and U.S. Publication Nos. 2003/0139364, 2003/185835,2004/0258698, 2004/0265351, 2004/076633, and 2005/0009858.

EXAMPLES

Objects and advantages of this invention are further illustrated by thefollowing examples, but the particular materials and amounts thereofrecited in these examples, as well as other conditions and details,should not be construed to unduly limit this invention.

Example 11-{[4-Amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexanol

Part A

To a mixture of 4-chloro-3-nitroquinoline (6.30 g, 30.2 mmol) indichloromethane (100 mL) at 0° C. was added triethylamine (0.1 mL). Tothe resulting solution was added 1-aminomethyl-1-cyclohexanolhydrochloride (5.00 g, 30.2 mmol), then triethylamine (4.1 mL) andtetrahydrofuran (THF, 20 mL). The mixture was allowed to warm to roomtemperature (rt) and more triethylamine (4.2 mL) was added. The yellowmixture was stirred overnight, then was concentrated to about half thevolume and heated at reflux for 1 hour (h). The mixture was concentratedand the solid was partitioned between 1 M aqueous NaOH (100 mL) andCH₂Cl₂ (200 mL). The organic layer was washed with water (2×50 mL) andbrine (50 mL), dried over MgSO₄, filtered, and concentrated to a yellowsolid that was crystallized from hot isopropanol to yield yellowcrystals (9.04 g). ¹H NMR analysis of the yellow crystals showed a 1:1.4mixture of isopropyl alcohol to1-{[(3-nitroquinolin-4-yl)amino]methyl}cyclohexanol. Based on the ¹H NMRresult, the mass of the1-{[(3-nitroquinolin-4-yl)amino]methyl}cyclohexanol in the mixture wascalculated (7.88 g, 87%). The product was used without furtherpurification in the next step.

Part B

A mixture of the 1-{[(3-nitroquinolin-4-yl)amino]methyl}cyclohexanolprepared above (87%, 7.00 g, 20.3 mmol) and 5% platinum on carbon (0.60g) in toluene (160 mL) and ethanol (20 mL) was hydrogenated at 20-30 psi(1.4×10⁵ to 2.1×10⁵ Pa) on a Parr apparatus for 2 h. The mixture wasfiltered through CELITE filter agent, which was rinsed with toluene. Thefiltrate was concentrated to a golden oil. The oil was concentratedtwice from toluene. To the oil was added CH₂Cl₂ (200 mL) and theresulting solution was cooled in an ice bath. Triethylamine (3.11 mL,22.3 mmol) was added followed by dropwise addition of ethoxyacetylchloride (88%, 2.96 g, 21.3 mmol). The solution was allowed to warm tort and stir for 1 h, during which time a precipitate formed. Thereaction mixture was concentrated to a yellow foam to which ethanol (200mL) and triethylamine (11 mL) were added. The resulting solution washeated at reflux for 13 h. The solution was concentrated to a yellowsolid, which was dissolved in CH₂Cl₂ (150 mL) and washed with water (50mL) and brine (75 mL). The organic layer was dried over MgSO₄, filtered,and concentrated to a solid that was crystallized from CDCl₃/CH₂Cl₂ toyield1-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexanolas pale orange crystals after drying (1.94 g, 28%).

Part C

To a solution of1-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexanol(1.90 g, 5.60 mmol) in CHCl₃ (43 mL) was added m-chloroperoxybenzoicacid (m-CPBA, 77% w/w, 1.26 g, 5.60 mmol) over 15 min. The reaction wasmonitored by thin layer chromatography (TLC) and more m-CPBA was addedover 1 h until the starting material was consumed. Water (40 mL) andsolid K₂CO₃ were added to the reaction mixture until the pH=10. Themixture was poured into a separatory funnel and extracted withchloroform, resulting in an emulsion. The aqueous layer was extractedwith chloroform three times. The combined organic layers were washedwith water and brine, dried over MgSO₄, filtered, and concentrated toyield a crude white solid (1.51 g). The white solid (1.51 g, 4.24 mmol)was dissolved in dichloromethane (25 mL) at rt and concentrated ammoniumhydroxide (16 mL) was added, followed by p-toluenesulfonyl chloride(TsCl, 0.81 g, 4.24 mmol). The mixture was stirred 1 day (d). Water (25mL) was added and the aqueous layer was extracted with dichloromethane(2×30 mL). The combined organic layers were washed with brine (25 mL)and were dried over MgSO₄, filtered, and concentrated. The crude productwas purified by flash chromatography (silica gel, gradient elution with98:1:1 CH₂Cl₂/MeOH/NH₄OH to 94:5:1 CH₂Cl₂/MeOH/NH₄OH) then crystallizedfrom acetonitrile to yield1-{[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexanolas pale orange crystals that were dried under high vacuum (0.32 g, 16%over two steps), mp 186-188° C. ¹H NMR (300 MHz, CDCl₃) δ 8.15 (dm,J=8.4 Hz, 1H), 7.81 (dm, J=8.4 Hz, 1H), 7.52 (m, 1H), 7.32 (m, 1H), 5.38(br s, 2H), 4.90 (br s, 2H), 4.74 (br s, 2H), 3.66 (q, J=7.0 Hz, 2H),3.00 (s, 1H), 1.71-1.52 (m, 10), 1.25 (t, J=7.0 Hz, 3H). MS (APCI) m/z355 (M+H⁺). Anal. calcd for C₂₀H₂₆O₂N₄: C, 67.77; H, 7.39; N, 15.81.Found: C, 67.52; H, 7.57; N, 15.78.

Example 2 Ethyl4-{[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}-4-hydroxypiperidine-1-carboxylate

Part A

To a solution of N-carbethoxy-4-piperidone (11.34 g, 66.24 mmol) innitromethane (5.3 mL) and ethanol (2 mL) was added a solution of sodiumethoxide in ethanol (2.67 M, 1.24 mL, 3.31 mmol). The mixture wasstirred for 5 min and a solution formed from which a solid precipitated.After 1.5 h, water (100 mL) was added and the solid was isolated byfiltration, washed with water (100 mL), and dried under vacuum with heatto yield the product ethyl4-hydroxy-4-(nitromethyl)piperidine-1-carboxylate as an off white solid,9.58 g (62%).

Part B

A mixture of ethyl 4-hydroxy-4-(nitromethyl)piperidine-1-carboxylate(5.2 g, 22.4 mmol) and 20% palladium hydroxide on carbon (0.50 g) inethanol (190 mL) was hydrogenated at 35 psi (2.4×10⁵ Pa) on a Parrapparatus for 5 h. The mixture was filtered through CELITE filter agentand the filtrate was concentrated. By ¹H NMR analysis, the reaction wasincomplete and the crude material was subjected to the reactionconditions again with fresh 20% palladium hydroxide on carbon (0.50 g)for another 24 h. The mixture was filtered through CELITE filter agentand the filtrate was concentrated to provide ethyl4-(aminomethyl)-4-hydroxypiperidine-1-carboxylate, which wasconcentrated from chloroform to remove residual ethanol before using inthe next reaction.

Part C

To a solution of ethyl 4-(aminomethyl)-4-hydroxypiperidine-1-carboxylate(22.4 mmol, prepared as described above) in dichloromethane (90 mL) wasadded triethylamine (3.12 mL, 22.4 mmol) and 4-chloro-3-nitroquinoline(3.71 g, 17.8 mmol). The mixture was sonicated and more dichloromethane(10 mL) was added in order to dissolve the 4-chloro-3-nitroquinoline.The solution was allowed to stand at rt for 18 h, then was poured into areparatory funnel and washed with 1 M NaOH (25 mL), water (2×30 mL), andbrine (30 mL). The organic layer was dried over MgSO₄, filtered, andconcentrated to yield a yellow foam that was crystallized fromisopropanol. The solid was isolated by filtration and dried to affordethyl4-hydroxy-4-{[(3-nitroquinolin-4-yl)amino]methyl}piperidine-1-carboxylateas yellow crystals (4.53 g, 54%).

Part D

A mixture of ethyl4-hydroxy-4-{[(3-nitroquinolin-4-yl)amino]methyl}piperidine-1-carboxylate(4.53 g, 12.1 mmol) and 5% platinum on carbon (0.50 g) in ethanol washydrogenated on a Parr apparatus at 40 psi (2.8×10⁵ Pa) for 2.5 h. Themixture was filtered through CELITE filter agent and the filtrate wasconcentrated. The residue was concentrated twice from toluene and oncefrom chloroform to remove the ethanol, then was dissolved indichloromethane (100 mL). To the solution at 0° C. was addedtriethylamine (1.86 mL, 13.3 mmol) and ethoxyacetyl chloride (88%, 1.77g, 12.7 mmol). After 1 h at rt, the solution was concentrated to ayellow foam and ethanol (120 mL) and triethylamine (6 mL) were added.The resulting solution was heated at reflux for 16 h and thenconcentrated in vacuo. The residue was partitioned betweendichloromethane and water. The organic layer was washed twice withbrine, dried over MgSO₄, filtered, and concentrated to a crude yellowoil. The oil was purified by flash chromatography (silica gel, gradientelution with 2-7% methanol/dichloromethane) to provide ethyl4-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}-4-hydroxypiperidine-1-carboxylateas a yellow foam (3.04 g, 61%).

Part E

To a solution of ethyl4-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}-4-hydroxypiperidine-1-carboxylate(2.43 g, 5.90 mmol) in dichloromethane (40 mL) at rt was added m-CPBA(55%, 1.85 g, 5.90 mmol). After 1 h, concentrated ammonium hydroxide (40mL) was added, followed by TsCl (1.18 g, 6.20). The reaction was stirredrapidly overnight. Water (40 mL) was added and the mixture was extractedthree times with dichloromethane. The combined organic phases werewashed with brine and dried over MgSO₄, filtered, and concentrated. Thecrude product was purified by flash chromatography (silica gel, 4%methanol/dichloromethane with 0.1% conc. NH₄OH). The appropriatefractions were concentrated to afford a yellow oil that was concentratedtwice from toluene to yield the product as a yellow foam, whichcrystallized from acetonitrile. The fine off-white crystals were driedunder vacuum at 65° C. to yield 0.71 g (28%) of ethyl4-{[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}-4-hydroxypiperidine-1-carboxylate,mp 165-167° C. ¹H NMR (CDCl₃, 300 MHz) δ 8.03 (dd, J=8.3, 0.8 Hz, 1H),7.80 (dm, J=8.3 Hz, 1H), 7.52 (m, 1H), 7.32 (m, 1H), 5.42 (br s, 2H),4.84 (s, 2H), 4.74 (br s, 2H), 4.10 (q, J=7.1 Hz, 2H), 4.00 (br s, 3H),3.71 (q, J=7.0 Hz, 2H), 3.08 (m, 2H), 1.85-1.30 (m, 4H), 1.26 (t, J=7.0Hz, 3H), 1.22 (t, J=7.2 Hz, 3H); MS (APCI) m/z 428 (M+H⁺); Anal. calcdfor C₂₂H₂₉N₅O₄: C, 61.81; H, 6.84; N, 16.38. Found: C, 61.77; H, 6.99;N, 16.44.

Example 31-{[4-Amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclopentanol

Part A

To a solution of cyclopentanone (40.0 mL, 452 mmol) in nitromethane (36mL) and ethanol (14 mL) was added a solution of sodium ethoxide inethanol (2.67 M, 8.5 mL, 23 mmol). The solution was stirred for 5 d atrt. Water (400 mL) was added and the mixture was extracted with ethylacetate (2×350 mL). The combined organic extracts were washed with water(2×200) and brine (200 mL), dried over MgSO₄, filtered, andconcentrated. The starting materials and solvent were removed from theproduct by distillation under reduced pressure to yield1-(nitromethyl)cyclopentanol as a yellow liquid, 8.3 g (13%).

Part B

A mixture of 1-(nitromethyl)cyclopentanol (8.3 g, 57.2 mmol) and 20%palladium hydroxide on carbon (0.6 g) in ethanol (150 mL) washydrogenated at 35 psi (2.4×10⁵ Pa) on a Parr apparatus for 1 d. Afterworkup, the reaction was not complete and was subjected to the reactionconditions again for 8 d with fresh catalyst. The mixture was filteredthrough CELITE filter agent and the filtrate was concentrated to yieldan oil that contained a 13:1 ratio of the desired amine product,1-(aminomethyl)cyclopentanol, to the corresponding hydroxylamine. Theoil was concentrated from toluene to remove the ethanol and used in thenext experiment without further purification.

Part C

To a solution of 1-(aminomethyl)cyclopentanol (approximately 55.2 mmol,prepared as described above) in dichloromethane (280 mL) was addedtriethylamine (7.76 mL, 55.7 mmol) and 4-chloro-3-nitroquinoline (9.22g, 44.3 mmol). The mixture was allowed to stand at rt over the weekend.A solid formed that was isolated by filtration. Two more crops of solidwere isolated from the mother liquor. The yellow solid was stirred inwater and filtered. The solid was washed with water multiple times andwas dried under vacuum with heat to give1-{[(3-nitroquinolin-4-yl)amino]methyl}cyclopentanol as yellow crystals(8.29 g, 52%).

Part D

A mixture of 1-{[(3-nitroquinolin-4-yl)amino]methyl}cyclopentanol (8.26g, 28.8 mmol) and 5% platinum on carbon (0.9 g) in ethanol (200 mL) washydrogenated on a Parr apparatus overnight. The mixture was filteredthrough CELITE filter agent and the filtrate was concentrated. Theproduct 1-{[(3-aminoquinolin-4-yl)amino]methyl}-1-cyclopentanol wasconcentrated from toluene and dichloromethane1-{[(3-aminoquinolin-4-yl)amino]methyl}cyclopentanol to remove ethanol,then used immediately in the next step.

Part E

To a solution of 1-{[(3-aminoquinolin-4-yl)amino]methyl}cyclopentanol(approximately 28.8 mmol, prepared as described above) indichloromethane (200 mL) at 0° C. was added triethylamine (4.41 mL, 31.6mmol) and ethoxyacetyl chloride (88%, 3.96 g, 30.2 mmol). After 3 h atrt, the solution was concentrated and ethanol (260 mL) and triethylamine(14 mL) were added. The resulting solution was heated at reflux for 18 hand then concentrated in vacuo. The residue was partitioned betweendichloromethane and water. The organic layer was washed with brine twiceand dried over MgSO₄, filtered, and concentrated to an oil that formed awhite solid when acetonitrile was added. The mixture was sonicatedbriefly and filtered. The white powder was dried under vacuum to providepure1-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclopentanol(4.55 g, 49% for three steps).

Part F

To a solution of1-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclopentanol(3.00 g, 9.22 mmol) in dichloromethane (60 mL) at rt was added m-CPBA(2.89 g, 9.22 mmol). After 1 h, concentrated ammonium hydroxide (60 mL)was added and the mixture was cooled in an ice bath. To the mixture wasadded TsCl (1.85 g, 9.68 mmol). The reaction was stirred rapidlyovernight at rt. Additional TsCl (0.21 g) was added in the morning andthe mixture was stirred 45 min. Water (75 mL) was added and the mixturewas extracted with dichloromethane (3×100 mL). The combined organicphases were washed with brine and dried over MgSO₄, filtered, andconcentrated. The resulting foam was treated with acetonitrile and awhite solid formed. The solid was recrystallized from acetonitrile anddried under vacuum to yield1-{[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclopentanolas fine tan crystals (1.57 g, 50%), mp 156.5-158.0° C. ¹H NMR (300 MHz,d₆-DMSO) δ 8.27 (dm, J=8.4 Hz, 1H), 7.59 (dd, J=8.4, 1.2 Hz, 1H), 7.40(m, 1H), 7.20 (m, 1H), 6.54 (br s, 2H), 4.89 (br s, 2H), 4.82 (br s,2H), 4.78 (s, 1H), 3.52 (q, J=7.0 Hz, 2H), 1.75-1.43 (m, 8H), 1.14 (t,J=7.0 Hz, 3H). MS (APCI) m/z 341 (M+H⁺). Anal. calcd for C₁₉H₂₄N₄O₂: C,67.04; H, 7.11; N, 16.46. Found: C, 67.12; H, 6.94; N, 16.36.

Example 4 tert-Butyl4-{[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}-4-hydroxypiperidine-1-carboxylate

Part A

To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (52.65 g, 264mmol) in nitromethane (21 mL) and ethanol (8 mL) was added a solution ofsodium ethoxide in ethanol (2.67 M, 5.0 mL, 13.4 mmol). The mixture wasstirred at rt and more ethanol (30 mL) was added. The mixture wassonicated for 15 min, stirred overnight, then sonicated again. To themixture was added water (400 mL). The solid was isolated by filtration,washed with water (300 mL), and dried to yield tert-butyl4-hydroxy-4-(nitromethyl)piperidine-1-carboxylate as a white solid,67.60 g (98%).

Part B

A mixture of tert-butyl4-hydroxy-4-(nitromethyl)piperidine-1-carboxylate (20.42 g, 78.4 mmol)and 20% palladium hydroxide on carbon (1.21 g) in ethanol (250 mL) washydrogenated at 40 psi (2.8×10⁵ Pa) for 3 d on a Parr apparatus. More20% palladium hydroxide on carbon (1.0 g) was added and thehydrogenation was continued for 2 more days. The mixture was filteredthrough CELITE filter agent and the filtrate was concentrated to providetert-butyl 4-(aminomethyl)-4-hydroxypiperidine-1-carboxylate, which wasconcentrated from toluene (200 mL) to remove residual ethanol before usein the next reaction.

Part C

To a solution of tert-butyl4-(aminomethyl)-4-hydroxypiperidine-1-carboxylate (78.4 mmol, preparedas described above) in dichloromethane (300 mL) was added triethylamine(11 mL, 79 mmol) and 4-chloro-3-nitroquinoline (12.7 g, 61.2 mmol). Themixture was stirred at rt for 1 h, then heated at reflux for 1 h. Thesolution was transferred to a separatory funnel and extracted with water(100 mL). The organic layer was isolated and upon standing a precipitateformed. The solid was isolated by filtration and washed withdichloromethane and water and dried. Additional solid precipitated fromthe mother liquor and was isolated. The two yellow solids were combinedand dried to yield tert-butyl4-hydroxy-4-{[(3-nitroquinolin-4-yl)amino]methyl}piperidine-1-carboxylate(20.23 g, 82%).

Part D

The starting material tert-butyl4-hydroxy-4-{[(3-nitroquinolin-4-yl)amino]methyl}piperidine-1-carboxylate(20.23 g, 50.3 mmol) was divided into two portions. To each portion wasadded ethanol (220 mL) and 5% platinum on carbon (1.1 g). Both portionswere hydrogenated on a Parr apparatus at 40 psi (2.8×10⁵ Pa) overnight.The mixtures were filtered through CELITE filter agent. The filtrateswere combined and concentrated to provide the product tert-butyl4-{[(3-aminoquinolin-4-yl)amino]methyl}-4-hydroxypiperidine-1-carboxylateas a brown oil. The product was concentrated twice from toluene and oncefrom chloroform and used in the subsequent experiment.

Part E

To a solution of tert-butyl4-{[(3-aminoquinolin-4-yl)amino]methyl}-4-hydroxypiperidine-1-carboxylate(50.3 mmol, prepared as described above) in dichloromethane (330 mL) at0° C. was added triethylamine (8 mL, 57.4 mmol) followed by dropwiseaddition of ethoxyacetyl chloride (88%, 6.59 g, 50.3 mmol). After 3 h atrt, more triethylamine (4 mL) and acid chloride (1.70 g) were added. Thesolution was stirred 1 h, then concentrated in vacuo to a foam andethanol (400 mL) and triethylamine (24 mL) were added. The resultingsolution was heated at reflux for 20 h and then concentrated in vacuo.The residue was dissolved in dichloromethane (600 mL) and washed withwater (2×200 mL) and brine (2×250 mL). The organic layer was dried twiceover MgSO₄, filtered, and concentrated to an oil. The oil was purifiedtwice by flash chromatography (silica gel, gradient elution with 3-5%methanol/dichloromethane) to provide tert-butyl4-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}-4-hydroxypiperidine-1-carboxylateas a yellow foam containing dichloromethane (13.13 g). Based on ¹H NMRintegration, the calculated amount of product was 12.59 g (57%).

Part F

To a solution of tert-butyl4-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}-4-hydroxypiperidine-1-carboxylate(96%, 10.0 g, 22.7 mmol) in dichloromethane (150 mL) at rt was addedm-CPBA (55%, 7.12 g, 22.7 mmol). After 1.5 h, the mixture was cooled to0° C. and concentrated ammonium hydroxide (150 mL) was added, followedby TsCl (4.54 g, 23.8 mmol). The reaction was stirred rapidly overnight.More TsCl (1.00 g and 0.47 g) was added as the mixture was stirred anadditional 6 h. Water (200 mL) was added and the mixture was extractedwith dichloromethane (3×200 mL). The combined organic phases were washedwith brine (3×250 mL) and dried over MgSO₄, filtered, and concentratedto a foam, which was crystallized from acetonitrile twice. The fineyellow crystals were dried under vacuum to yield 1.60 g (15%) oftert-butyl4-{[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}-4-hydroxypiperidine-1-carboxylate,mp 195-197° C. ¹H NMR (CDCl₃, 300 MHz) δ 8.04 (dm, J=8.3 Hz, 1H), 7.82(dm, J=8.3 Hz, 1H), 7.53 (m, 1H), 7.31 (m, 1H), 5.40 (br s, 2H), 4.85(s, 2H), 4.75 (br s, 2H), 3.93 (br s, 3H), 3.72 (q, J=7.0 Hz, 2H), 3.03(m, 2H), 1.76 (m, 2H), 1.49-1.40 (m, 2H), 1.42 (s, 9H), 1.27 (t, J=7.0Hz, 3H); MS (APCI) m/z 456 (M+H⁺); Anal. calcd for C₂₄H₃₃N₅O₄: C, 63.28;H, 7.30; N, 15.37. Found: C, 63.32; H, 7.53; N, 15.39.

Example 54-{[4-Amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}piperidin-4-oldihydrochloride

To a solution of tert-butyl4-{[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}-4-hydroxypiperidine-1-carboxylate(0.720 g, 1.62 mmol, prepared as described in Example 4) in ethanol (10mL) was added 4.3 M HCl in ethanol (2 mL). The solution was heated at65° C. for 1.5 h. After the mixture cooled to rt, a solid was isolatedby filtration. The solid was washed with diethyl ether and dried underreduced pressure at 100° C. to afford4-{[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}piperidin-4-oldihydrochloride as a 0.5 hydrate and as a white solid, mp>260° C. MS(APCI) m/z 356 (M+H)⁺; Anal. calcd for C₁₉H₂₅N₅O₂.2HCl.0.5 H₂0: C,52.18; H, 6.45; N, 16.01. Found: C, 52.32; H, 6.40; N, 15.90.

Example 64-{[4-Amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}-1-(methylsulfonyl)piperidin-4-ol

To the 1.5 hydrate of4-{[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}piperidin-4-oldihydrochloride (1.00 g, 2.20 mmol, prepared in a similar manner asdescribed in Example 5) was added chloroform (150 mL) and triethylamine(1.1 mL, 7.7 mmol). The starting material did not completely dissolve.To the mixture was added methanesulfonyl chloride (MeSO₂Cl, 0.19 mL,2.42 mmol) and more triethylamine (0.3 mL). After 4 h at rt, moreMeSO₂Cl (0.06 mL) and triethylamine (0.3 mL) were added and the mixturewas stirred overnight. Pyridine (20 mL) and dimethylformamide (DMF, 20mL) were added, followed by MeSO₂Cl (0.06 mL). To the mixture was addedmethanesulfonyl anhydride (115 mg) and the mixture was allowed to standfor 2 d. The mixture was filtered, and the filtrate was concentrated toapproximately 25 mL, which was diluted with chloroform (400 mL) andextracted with 1 M NaOH (2×150 mL), water (150 mL), and brine (200 mL).The organic phase was dried over Na₂SO₄, filtered, and concentrated to ayellow oil. The crude product was purified by flash chromatography(silica gel, eluted with 1% CMA/CHCl₃ where CMA is a solution comprisedof 80:18:2 chloroform/methanol/concentrated ammonium hydroxide) toafford4-{[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}-1-(methylsulfonyl)piperidin-4-olas a white solid (0.34 g, 36%) after drying at 60° C. under reducedpressure, mp 254-256° C. ¹H NMR (300 MHz, DMSO-d₆) δ 8.35 (dm, J=8.4 Hz,1H), 7.59 (dd, J=8.4, 1.4 Hz, 1H), 7.41 (m, 1H), 7.23 (m, 1H), 6.57 (brs, 2H), 5.16-4.60 (br m, 4H), 5.05 (s, 1H), 3.53 (q, J=7.0 Hz, 2H),3.37-3.27 (br s, 2H), 2.89-2.79 (m, 2H), 2.81 (s, 3H), 1.93-1.78 (m,2H), 1.62-1.29 (br s, 2H), 1.14 (t, J=7.0 Hz, 3H); MS (APCI) m/z 434(M+H)⁺; Anal. calcd for C₂₀H₂₇N₅O₄S: C, 55.41; H, 6.28; N, 16.15; S,7.40. Found: C, 55.21; H, 6.11; N, 16.35; S, 7.37.

Example 72-(Ethoxymethyl)-1-[(1-methoxycyclopentyl)methyl]-1H-imidazo[4,5-c]quinolin-4-amine

Part A

To a solution of1-{[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclopentanol(1.19 g, 3.66 mmol, prepared as described in Example 3) in THF (18 mL)at rt was added sodium hydride (60% dispersion in oil, 161 mg, 4.03mmol). The mixture was stirred for 1 h and iodomethane (0.25 mL, 4.03mmol) was added. The mixture was heated to 50° C. for 3 h and then wasleft to stand at rt overnight. More sodium hydride (60% dispersion inoil, 80 mg) and iodomethane (0.13 mL) were added. The mixture was heatedfor 2 h, then water was added and the mixture was extracted three timeswith ethyl acetate. The combined organic extracts were washed with brineand dried over Na₂SO₄, filtered and concentrated to an oil. The crudeproduct was purified by flash chromatography (silica gel, eluted withethyl acetate) to yield2-(ethoxymethyl)-1-[(1-methoxycyclopentyl)methyl]-1H-imidazo[4,5-c]quinolineas a yellow oil (0.30 g, 24%).

Part B

To a solution of2-(ethoxymethyl)-1-[(1-methoxycyclopentyl)methyl]-1H-imidazo[4,5-c]quinoline(0.30 g, 0.88 mmol) in dichloromethane at rt was added m-CPBA (278 mg,0.88 mmol). The solution was stirred for 1.5 h and concentrated ammoniumhydroxide (5.73 mL) was added and the mixture was cooled in an ice bath.To the mixture was added TsCl (176 mg, 0.924 mmol). The mixture wasstirred 3 h at rt. Water (10 mL) was added and the mixture was extractedwith dichloromethane (3×20 mL). The combined organics were washed twicewith brine, dried over Na₂SO₄, filtered, and concentrated to a yellowoil. The crude product was purified by flash chromatography (silica gel,gradient elution with 1-10% CMA/CHCl₃). The purified product wascrystallized from acetonitrile to provide2-(ethoxymethyl)-1-[(1-methoxycyclopentyl)methyl]-1H-imidazo[4,5-c]quinolin-4-amineas off white crystals (0.122 g, 39%) after vacuum drying at 80° C., mp148.0-150.0° C.

¹H NMR (300 MHz, CDCl₃) δ 8.13 (dd, J=8.4, 1.4 Hz, 1H), 7.81 (dd, J=8.4,1.4 Hz, 1H), 7.51 (ddd, J=8.4, 7.0, 1.4 Hz, 1H), 7.30 (ddd, J=8.4, 7.0,1.4 Hz, 1H), 5.39 (br s, 2H), 4.94 (s, 2H), 4.92 (s, 2H), 3.57 (q, J=7.0Hz, 2H), 3.17 (s, 3H), 1.92-1.56 (m, 8H), 1.23 (t, J=7.0 Hz, 3H); MS(APCI) m/z 355 (M+H⁺); Anal. calcd for C₂₀H₂₆N₄O₂: C, 67.77; H, 7.39; N,15.81. Found: C, 67.76; H, 7.45; N, 15.76.

Example 81-{[4-Amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclobutanol

Part A

To a solution of cyclobutanone (10.0 g, 143 mmol) and nitromethane (12mL) in ethanol (10 mL) was added sodium ethoxide in ethanol (2.67 M, 2.7mL, 7.2 mmol). The mixture was stirred for 6 d at rt. Water was addedand the mixture was extracted thrice with ethyl acetate. The organicphases were combined, washed with water and brine, dried over Na₂SO₄,filtered, and concentrated. The volatiles were removed by distillationunder vacuum to provide 1-(nitromethyl)cyclobutanol as a yellow liquid(8.51 g, 45%).

Part B

A mixture of 1-(nitromethyl)cyclobutanol (8.2 g, 62.5 mmol) and 20%palladium hydroxide on carbon (1.0 g) in ethanol (200 mL) washydrogenated at 40 psi (2.8×10⁵ Pa) on a Parr apparatus for 6 d. More20% palladium hydroxide on carbon (1.2 g) was added and the mixture washydrogenated at 40 psi (2.8×10⁵ Pa) for an additional 5 d. The mixturewas filtered through CELITE filter agent, which was rinsed with ethanol.The filtrate was concentrated to an oil that was concentrated fromdichloromethane and chloroform to remove residual ethanol.1-(Aminomethyl)cyclobutanol was obtained as an off white solid (6.15 g)that was used without further purification in the next step.

Part C

To a solution of 1-(aminomethyl)cyclobutanol (62.5 mmol) indichloromethane (312 mL) was added triethylamine (8.71 mL, 62.5 mmol)and 4-chloro-3-nitroquinoline (13.04 g, 62.5 mmol). More triethylamine(3 mL) was added almost immediately. The reaction was stirred under N₂for 10 d at rt, then was diluted with dichloromethane and washed with 1M aqueous NaOH. A solid formed and was isolated by filtration. Theorganic layer was washed with water and brine, dried over Na₂SO₄,filtered, and concentrated to a solid that was crystallized fromisopropanol. The resulting crystals were combined with the solid thatwas isolated from the extraction and the mixture was triturated with hotisopropanol. The solid was isolated by filtration, washed with diethylether, and air dried to yield1-{[(3-nitroquinolin-4-yl)amino]methyl}cyclobutanol as yellow crystals.(12.83 g, 75%).

Part D

A mixture of 1-{[(3-nitroquinolin-4-yl)amino]methyl}cyclobutanol (6.32g, 23.1 mmol) and 20% palladium hydroxide on carbon (0.60 g) in EtOH(100 mL) was hydrogenated overnight on a Parr apparatus at 40 psi(2.8×10⁵ Pa). The mixture was filtered through CELITE filter agent,which was rinsed several times with EtOH, and the filtrate wasconcentrated to provide1-{[(3-aminoquinolin-4-yl)amino]methyl}cyclobutanol as a pale yellowsolid (5.66 g). The solid was concentrated from toluene and chloroformto remove ethanol before using directly in the next reaction.

Part E

To a mixture of 1-{[(3-aminoquinolin-4-yl)amino]methyl}cyclobutanol(23.1 mmol, prepared as described in Part D) in dichloromethane (154 mL)and triethylamine (3.54 mL, 25.4 mmol) at 0° C. was added chloroform(100 mL). The mixture was allowed to warm to rt and approximately twothirds of the starting material dissolved. To the mixture was slowlyadded ethoxyacetyl chloride (88%, 3.1 g, 24.3 mmol). The solution wasstirred at rt for 2 h. More triethylamine (2 mL) and ethoxyacetylchloride (88%, 1.0 g) were added. After an additional 16 h, the reactionsolution was concentrated in vacuo. To the residue was added ethanol(190 mL) and triethylamine (13 mL). The resulting solution was heated atreflux for 20 h and then concentrated in vacuo to a yellow solid. Thesolid was partitioned between dichloromethane (400 mL) and water (100mL). The organic layer was washed with water (100 mL) and brine (100mL). The organic layer was dried over MgSO₄, filtered, and concentrated.The crude product was crystallized from acetonitrile and the crystalswere isolated by filtration to provide1-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclobutanol(4.52 g, 63%).

Part F

To a solution of1-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclobutanol(4.05 g, 13.0 mmol) in dichloromethane (85 mL) at rt was added m-CPBA(55%, 4.08 g, 13.0 mmol). After 1 h, concentrated ammonium hydroxide (85mL) was added, followed by TsCl (2.73 g, 14.3 mmol). The reaction wasstirred rapidly for 2 d. More TsCl (0.25 g) was added and the mixturewas stirred one day more. The layers were separated. Water was added tothe aqueous layer, which was extracted twice with dichloromethane. Thecombined organic layers were washed with water and brine, dried overNa₂SO₄, filtered, and concentrated to a pale yellow foam. Acetonitrilewas added to the foam, causing a solid to form. The solid was trituratedwith hot acetonitrile to yield an off white solid that was crystallizedfrom acetonitrile/dichloromethane. Pale yellow crystals were isolated byfiltration and dried under vacuum 80° C. to yield 1.81 g (43%) of1-{[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclobutanol,mp 174-175° C. ¹H NMR (CDCl₃, 300 MHz) δ 8.23 (dd, J=8.3, 1.4 Hz, 1H),7.78 (dd, J=8.4, 1.4 Hz, 1H), 7.50 (ddd, J=8.4, 7.0, 1.4 Hz, 1H), 7.31(ddd, J=8.4, 7.0, 1.4 Hz, 1H), 5.41 (br s, 2H), 4.893 (s, 2H), 4.886 (s,2H), 3.64 (q, J=7.0 Hz, 2H), 3.50 (br s, 1H), 2.35-2.27 (m, 2H),2.10-1.78 (m, 4H), 1.25 (t, J=7.0 Hz, 3H); MS (APCI) m/z 327 (M+H⁺);Anal. calcd for C₁₈H₂₂N₄O₂: C, 66.24; H, 6.79; N, 17.16. Found: C,66.02; H, 6.87; N, 17.09.

Example 98-{[4-Amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}-1,4-dioxaspiro[4.5]decan-8-ol

Part A

To a solution of 1,4-cyclohexanedione mono-ethylene ketal (30.0 g, 192mmol) and nitromethane (15.6 mL, 288 mmol) in ethanol (18 mL) was addeda solution of sodium ethoxide in ethanol (2.67 M, 3.4 mL, 9.6 mmol). Thesolution was stirred at room temperature (rt) for 5 days (d), then wasconcentrated under reduced pressure to a brown oil that was partitionedbetween water (100 mL) and dichloromethane (100 mL). The aqueous layerwas extracted with dichloromethane (3×100 mL). The organic layers werecombined, dried over Na₂SO₄, filtered, and concentrated to a light brownoil. Purification by flash chromatography (silica gel, 40% ethylacetate/hexanes) provided the product8-(nitromethyl)-1,4-dioxaspiro[4.5]decan-8-ol as a clear oil (16.7 g,40%) that slowly formed clear crystals overnight.

Part B

A mixture of 8-(nitromethyl)-1,4-dioxaspiro[4.5]decan-8-ol (16.0 g, 13.8mmol) and 20% palladium hydroxide on carbon (3.2 g) in ethanol (160 mL)was hydrogenated at 50 psi (3.5×10⁵ Pa) for 5 d on a Parr apparatus. Thereaction mixture was filtered through CELITE filter agent and thefiltrate was concentrated to give8-(aminomethyl)-1,4-dioxaspiro[4.5]decan-8-ol as a clear oil (13.7 g,99%) that solidified upon standing overnight.

Part C

To a 0° C. solution of 4-chloro-3-nitroquinoline (7.50 g, 36.0 mmol) andtriethylamine (7.5 mL, 54 mmol) in dichloromethane (150 mL) was added8-(aminomethyl)-1,4-dioxaspiro[4.5]decan-8-ol (8.10 g, 43.1 mmol). Thereaction was allowed to warm to rt and stir overnight, then wasconcentrated under reduced pressure to yield a yellow solid. The solidwas stirred in water (500 mL) and was isolated by filtration, driedunder vacuum, and recrystallized from toluene (280 mL) to yield8-{[(3-nitroquinolin-4-yl)amino]methyl}-1,4-dioxaspiro[4.5]decan-8-ol asbright yellow crystals (12.3 g, 72%).

Part D

A mixture of8-{[(3-nitroquinolin-4-yl)amino]methyl}-1,4-dioxaspiro[4.5]decan-8-ol(12.0 g, 33.4 mmol) and 5% platinum on carbon (1.2 g) in acetonitrile(120 mL) was hydrogenated at 50 psi (3.5×10⁵ Pa) for 4 hours (h) on aParr apparatus. The reaction mixture was filtered through CELITE filteragent with dichloromethane and ethanol. The filtrate was concentrated togive8-{[(3-aminoquinolin-4-yl)amino]methyl}-1,4-dioxaspiro[4.5]decan-8-ol asa orange solid (10.9 g, 99%).

Part E

A solution of ethoxyacetyl chloride (4.38 g, 35.7 mmol) indichloromethane (50 mL) was added to a 0° C. solution of8-{[(3-aminoquinolin-4-yl)amino]methyl}-1,4-dioxaspiro[4.5]decan-8-ol(10.7 g, 32.5 mmol) and triethylamine (4.98 mL, 35.7 mmol) indichloromethane (250 mL). After one hour, the solution was allowed towarm to rt and stir for 2 d. More ethoxyacetyl chloride (0.15equivalent) was added. After two hours, the solution was transferred toa separatory funnel and washed with water (200 mL). The organic layerwas dried with Na₂SO₄, filtered, and concentrated under reduced pressureto yield an orange solid. The solid was dissolved in ethanol (150 mL)and triethylamine (13.6 mL, 97.4 mmol) was added. The solution washeated at reflux for 16 h. The volatiles were removed under reducedpressure to yield a brown oil that was crystallized from isopropanol toyield8-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}-1,4-dioxaspiro[4.5]decan-8-olas off-white crystals (2.50 g) and a second crop (1.50 g) of crystals. Athird crop (4.91 g) was isolated after recrystallization of the motherliquor from ethyl acetate. A total of 8.91 g (69%) of8-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}-1,4-dioxaspiro[4.5]decan-8-olwas isolated.

Part F

To a solution of8-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}-1,4-dioxaspiro[4.5]decan-8-ol(3.0 g, 10.1 mmol) in chloroform at rt was added m-chloroperbenzoic acid(m-CPBA, 3.6 g, 12.1 mmol). After 2 h, the solution was transferred to aseparatory funnel and washed with 10% Na₂CO₃ (100 mL). The aqueous layerwas back-extracted with chloroform. The organic layers were combined,dried over MgSO₄, filtered, and concentrated under reduced pressure toan off-white solid. To the solid was added dichloromethane (30 mL) andconcentrated ammonium hydroxide (10 mL). p-Toluenesulfonyl chloride(TsCl, 1.69 g, 8.85 mmol) was added over 5 minutes (min). After 3 h, thereaction mixture was diluted with water (100 mL) and extracted withdichlormethane (3×100 mL). The organic layers were combined, dried overMgSO₄, filtered, and concentrated under reduced pressure. The crudeproduct was purified by flash chromatography (silica gel, 20% methanolin ethyl acetate) and was recrystallized from isopropanol (20 mL). Thecrystals were dissolved in methanol and concentrated under reducedpressure and dried in a vacuum oven at 80° C. to provide8-{[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}-1,4-dioxaspiro[4.5]decan-8-ol(1.03 g, 33%) as a light tan frothy solid, mp 207-209° C. ¹H NMR (300MHz, CDCl₃) δ 8.12 (m, 1H), 7.79 (m, 1H), 7.49 (m, 1H), 7.31 (m, 1H),5.39 (br s, 2H), 4.85 (s, 2H), 4.74 (s, 2H), 3.90 (m, 4H), 3.65 (q,J=7.0 Hz, 2H), 3.21 (br s, 1H), 2.01-1.45 (m, 8H), 1.24 (t, J=6.9 Hz,3H); MS (APCI) m/z 413 (M+H)⁺; Anal. Calcd for C₂₂H₂₈N₄O₄.0.25H₂O: C,63.37; H, 6.89; N, 13.44. Found: C, 63.32; H, 6.85; N, 13.41.

Example 104-{[4-Amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}tetrahydro-2H-pyran-4-ol

Part A

A solution of tetrahydro-4H-pyran-4-one (45.0 g, 449 mmol) andnitromethane (36.5 mL, 674 mmol) in ethanol (27 mL) was treated with asolution of sodium ethoxide in ethanol (2.67 M, 8.40 mL, 22.5 mmol)using the method described in Part A of Example 9. The reaction mixturewas transferred to a reparatory funnel and water (450 mL) was added. Themixture was extracted with ethyl acetate (3×900 mL). The organic layerswere combined, dried over MgSO₄, filtered, and concentrated to a lightbrown oil. Ethyl acetate/hexanes was added and pale brown crystalsformed that were isolated by filtration and dried to provide4-(nitromethyl)tetrahydro-2H-pyran-4-ol (24.4 g, 34%).

Part B

4-(Nitromethyl)tetrahydro-2H-pyran-4-ol (23.3 g, 145 mmol) washydrogenated according to the method described in Part B of Example 9 toprovide 4-(aminomethyl)tetrahydro-2H-pyran-4-ol as a clear oil (19.0 g,100%).

Part C

4-Chloro-3-nitroquinoline (12.0 g, 57.5 mmol) and was reacted with4-(aminomethyl)tetrahydro-2H-pyran-4-ol (11.3 g, 86.3 mmol) according tothe method described in Part C of Example 9. The crude yellow solid wasstirred in water (100 mL) and was isolated by filtration, dried undervacuum, and recrystallized from 1,2-dichloroethane to yield4-{[(3-nitroquinolin-4-yl)amino]methyl}tetrahydro-2H-pyran-4-ol asbright yellow crystals (15.6 g, 90%).

Part D

A mixture of4-{[(3-nitroquinolin-4-yl)amino]methyl}tetrahydro-2H-pyran-4-ol (9.00 g,29.7 mmol) and 5% platinum on carbon (0.90 g) in acetonitrle (180 mL)was hydrogenated according to the method described in Part D of Example9 to yield4-{[(3-aminoquinolin-4-yl)amino]methyl}tetrahydro-2H-pyran-4-ol as abrown solid (7.60 g, 94%).

Part E

4-{[(3-Aminoquinolin-4-yl)amino]methyl}tetrahydro-2H-pyran-4-ol (7.50 g,27.4 mmol) was reacted with ethoxyacetyl chloride (3.70 g, 30.1 mmol)and the resulting product was cyclized according to the method describedin Part E of Example 9 to provide4-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}tetrahydro-2H-pyran-4-olas pale tan crystals (7.50 g, 76%) after crystallization from ethanol.

Part F

To a solution of4-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}tetrahydro-2H-pyran-4-ol(3.0 g, 8.79 mmol) in chloroform (60 mL) at rt was addedm-chloroperbenzoic acid (m-CPBA, 3.2 g, 10.5 mmol). After 2 h, thesolution was transferred to a separatory funnel and washed with 10%Na₂CO₃ (100 mL). The aqueous layer was back-extracted with chloroform.The organic layers were combined, dried over MgSO₄, filtered, andconcentrated under reduced pressure to yield a light orange solid. Tothe solid was added dichloromethane (30 mL). Trichloroacetyl isocyanate(1.05 mL, 8.79 mL) was added dropwise. After 1 h, additionaltrichloroacetyl isocyanate (0.3 equivalent) was added. After 1 h, thevolatiles were removed under reduced pressure and the residue wasdissolved in methanol (30 mL). A solution of sodium methoxide inmethanol (25%, 5.0 mL) was added and the solution stirred overnight atrt and concentrated under reduced pressure. The residue was partitionedbetween dichloromethane (100 mL) and water (100 mL). The aqueous layerwas extracted with dichlormethane (2×100 mL). The organic layers werecombined, dried over MgSO₄, filtered, and concentrated under reducedpressure. The crude product was purified by flash chromatography (silicagel, eluted with 10% methanol/dichloromethane) to afford a clear oilthat was triturated with isopropanol (50 mL) to afford white crystals.The crystals were dissolved in methanol, concentrated under reducedpressure, and dried in a vacuum oven at 80° C. to provide4-{[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}tetrahydro-2H-pyran-4-ol(1.27 g, 41%) as a white frothy solid, mp 212-214° C. ¹H NMR (300 MHz,DMSO-d₆) δ 8.33 (dd, J=8.3, 1.1 Hz, 1H), 7.60 (dd, J=8.3, 1.2 Hz, 1H),7.40 (ddd, J=8.3, 7.0, 1.4 Hz, 1H), 7.22 (ddd, J=8.3, 7.0, 1.4 Hz, 1H),6.37 (br s, 2H), 4.90 (br s, 2H), 4.88 (s, 1H), 4.70 (br s, 2H),3.62-3.47 (m, 6H), 1.87-1.74 (m, 2H), 1.28 (m, 2H), 1.14 (t, J=7.0 Hz,3H); MS (APCI) m/z 357 (M+H)⁺; Anal. Calcd for C₁₉H₂₄N₄O₃: C, 64.03; H,6.79; N, 15.72. Found: C, 63.75; H, 7.06; N, 15.71.

Example 114-[(4-Amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]tetrahydro-2H-pyran-4-ol

Part A

A solution of4-{[(3-aminoquinolin-4-yl)amino]methyl}tetrahydro-2H-pyran-4-ol(prepared as described in Part D of Example 10, 8.0 g, 29.3 mmol),triethylorthoacetate (5.6 mL, 30.7 mmol), and pyridine hydrochloride(1.0 g) in toluene (160 mL) was heated at reflux for 2 h, then wasstirred at rt for 2 d. More triethylorthoacetate was added and thesolution was heated at reflux. The solution was allowed to cool to rtand was washed with 10% aqueous Na₂CO₃ (100 mL). The aqueous layer wasback-extracted with a solution of 10% methanol in dichloromethane(10×100 mL). The organic layers were combined, dried with MgSO₄,filtered, and concentrated under reduced pressure to afford a brownsolid (8.7 g). The solid was dissolved in dichloromethane (50 mL). Tothe solution was added triethylamine (4.00 mL, 28.5 mmol). The solutionwas cooled to 0° C. and acetyl chloride (0.68 mL, 9.5 mmol) was addeddropwise. After three days at rt, the reaction was concentrated underreduced pressure. The residue was dissolved in pyridine (80 mL) andpyridine hydrochloride (5.0 g) was added. The reaction was heated toreflux for 4 h and concentrated under reduced pressure. The resultingbrown oil was dissolved in 10% Na₂CO₃ (200 mL) and was extractedovernight with chloroform in a continuous extractor. The chloroformlayer was reduced to a light brown solid that was purified by flashchromatography (silica gel, eluted with 15% methanol in dichloromethane)to afford4-[(2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]tetrahydro-2H-pyran-4-ol(6.2 g, 71%) as a tan solid.

Part B

4-[(2-Methyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]tetrahydro-2H-pyran-4-ol(3.0 g, 10.1 mmol) was converted to4-[(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]tetrahydro-2H-pyran-4-ol(0.28 g, 9%) according to the method described in Part F of Example 10.The product4-[(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]tetrahydro-2H-pyran-4-olwas purified by flash chromatography (silica gel, eluted with 30%methanol/ethyl acetate) and crystallized from methanol/water to affordwhite crystals, mp>250° C. ¹H NMR (300 MHz, DMSO-d₆) δ 8.32 (m, 1H),7.58 (dd, J=8.3, 1.2 Hz, 1H), 7.37 (ddd, J=8.3, 7.0, 1.2 Hz, 1H), 7.20(ddd, J=8.3, 7.0, 1.3 Hz, 1H), 6.44 (br s, 2H), 4.90 (s, 1H), 4.55 (brs, 2H), 3.65-3.46 (m, 4H), 2.66 (s, 3H), 1.88-1.74 (m, 2H), 1.40-1.24(m, 2H); MS (APCI) m/z 313 (M+H)⁺; Anal. Calcd for C₁₇H₂₀N₄O₂.0.40H₂O:C, 63.89; H, 6.56; N, 17.53. Found: C, 63.96; H, 6.69; N, 17.61.

Example 121-{3-[4-Amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}cyclohexanol

Part A

A solution of allyl magnesium bromide in diethyl ether (1 M, 53 mL, 53mmol) was added dropwise to a solution of cyclohexanone (5.00 mL, 48.2mmol) in diethyl ether at 0° C. The cloudy white reaction mixture wasallowed to stir at rt overnight. The reaction was quenched withsaturated aqueous NH₄Cl (100 mL) and diluted with water (20 mL) anddiethyl ether (50 mL). The mixture was transferred to a separatoryfunnel and the layers were separated. The aqueous layer was extractedwith diethyl ether (2×50 mL). The combined organic layers were washedwith brine (100 mL), dried over MgSO₄, filtered, and concentrated toafford a 1-allylcyclohexanol as a colorless oil (6.97, 103%) thatcontained a small amount of diethyl ether.

Part B

Pyridine (11.7 mL, 145 mmol), 4-dimethylaminopyridine (DMAP, 0.59 g,4.82 mmol) and tert-butyldimethylsilyl chloride (8.71 g, 57.8 mmol) wereadded to a solution of 1-allylcyclohexanol (48.2 mmol) in acetonitrile(120 mL). The reaction was heated at reflux overnight, then cooled to rtand concentrated to about 50 mL under reduced pressure. The solution wascooled to 0° C. and tert-butyldimethylsilyl triflate (13.3 mL, 57.8mmol) was added. After the solution had stirred overnight at rt,additional tert-butyldimethylsilyl triflate (5.00 mL) was added and thesolution was stirred for 6 h longer. The reaction was quenched withsaturated aqueous sodium bicarbonate (120 mL) and extracted withdichloromethane (100 mL, then 2×75 mL). The combined organic layers weredried over MgSO₄, filtered, and concentrated to give a colorless oilthat was purified on a on a HORIZON High-Performance FlashChromatography (HPFC) instrument (available from Biotage, Inc,Charlottesville, Va., USA) (silica gel, gradient elution with 0-5% ethylacetate/hexanes) to afford[(1-allylcyclohexyl)oxy](tert-butyl)dimethylsilane as a colorless oil(11.96 g, 97%).

Part C

A solution of borane in tetrahydrofuran (1 M, 15.7 mL, 15.7 mmol) wasadded to a solution of[(1-allylcyclohexyl)oxy](tert-butyl)dimethylsilane (8.00 g, 31.4 mmol)in tetrahydrofuran. After 2 h, water (5 mL) was added dropwise, followedby 3 M NaOH (6 mL), followed by dropwise addition of 30% aqueoushydrogen peroxide (6 mL). The mixture was stirred at rt for 1 h, thenwas diluted with diethyl ether (100 mL) and water (70 mL). The layerswere separated and the aqueous layer was extracted with diethyl ether(2×35 mL). The combined organic layers were washed with brine (90 mL),dried over MgSO₄, filtered, and concentrated to yield a colorless oilthat was purified using HPFC (silica gel, gradient elution with 2-30%ethyl acetate/hexanes) to afford pure3-(1-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)propan-1-ol (6.80 g,79%).

Part D

Methanesulfonyl chloride (2.1 mL, 27.4 mmol) was added dropwise to asolution of 3-(1-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)propan-1-ol(6.80 g, 24.9 mmol) and triethylamine (4.20 mL, 29.9 mmol) indichloromethane (100 mL) at 0° C. The solution was stirred for 2 h at 0°C., then was diluted with dichloromethane (20-25 mL) and saturatedaqueous sodium bicarbonate (70 mL). The layers were separated and theaqueous layer was extracted with dichloromethane (40 mL). The combinedorganic layers were dried over MgSO₄, filtered, and concentrated toafford 3-(1-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)propylmethanesulfonate as a pale oil that was used directly in the next step.

Part E

Sodium azide (1.78 g, 27.4 mmol) was added to a solution of3-(1-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)propyl methanesulfonate(prepared as described in Part D, 24.9 mmol) in dimethylformamide (100mL). The reaction mixture was stirred for 2.5 d and additional sodiumazide (160 mg) was added. The mixture was stirred an additional 1 d,then was diluted with diethyl ether (250 mL) and washed with water (3×75mL). The combined aqueous layers were back-extracted with diethyl ether(50 mL). The combined organic layers were washed with brine (100 mL),dried over MgSO₄, filtered, and concentrated to afford{[1-(3-azidopropyl)cyclohexyl]oxy}(tert-butyl)dimethylsilane (7.05 g,95% over two steps) as a pale yellow oil. A mixture of the{[1-(3-azidopropyl)cyclohexyl]oxy}(tert-butyl)dimethylsilane (7.05 g,23.7 mmol) and 5% palladium on carbon (0.71 g) in ethanol (100 mL) washydrogenated at 30 psi (2.1×10⁵ Pa) for 4 h on a Parr apparatus. Thereaction mixture was filtered through CELITE filter agent, which wasrinsed afterwards with dichloromethane, and the filtrate wasconcentrated to give3-(1-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)propan-1-amine as a paleyellow oil (6.57 g, 102%) that contained a trace amount of solvent.

Part F

4-Chloro-3-nitroquinoline (0.700 g, 3.37 mmol) was added in two portionsto a solution of3-(1-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)propan-1-amine (0.960 g,3.54 mmol) and triethylamine (0.610 mL, 4.38 mmol) in dichloromethane(15 mL) at 0° C. After 30 min, the reaction was allowed to warm to rtand stir overnight. The mixture was diluted with dichloromethane (40 mL)and was washed with saturated aqueous sodium bicarbonate (30 mL). Theaqueous layer was extracted with dichloromethane (20 mL). The combinedorganic layers were dried over MgSO₄, filtered, and concentrated toafford a yellow solid. The crude product was purified using HPFC (silicagel, gradient elution with 0-2% ethyl acetate/hexanes) to yieldN-[3-(1-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)propyl]-3-nitroquinolin-4-amineas a bright yellow solid (1.40 g, 93%).

Part G

A mixture ofN-[3-(1-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)propyl]-3-nitroquinolin-4-amine(1.40 g, 3.16 mmol) and 5% platinum on carbon (0.14 g) in ethyl acetate(15 mL) was hydrogenated at 30 psi (2.1×10⁵ Pa) for 2 h on a Parrapparatus. The reaction mixture was filtered through CELITE filteragent, which was rinsed with ethyl acetate afterwards, and the filtratewas concentrated to giveN⁴-[3-(1-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)propyl]quinoline-3,4-diamineas an orange colored gum. The gum was dissolved in dichloromethane (15mL) and the solution was cooled to 0° C. Ethoxyacetyl chloride (0.350mL, 3.48 mmol) was added dropwise over 2 min. The reaction was allowedto stir at 0° C. for 1 h, then was concentrated in vacuo to yieldN-(4-{[3-(1-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)propyl]amino}quinolin-3-yl)-2-ethoxyacetamidehydrochloride as a yellow solid. The yellow solid was dissolved inethanol (12 mL) and 2 M NaOH (2.4 mL, 4.8 mmol) was added. The reactionwas heated at 60° C. for 1 h. The reaction was cooled to rt and thesolvent was removed in vacuo. The residue was partitioned betweendichloromethane (50 mL) and water (30 mL), and 1 M HCl was added to themixture until the pH=7-8. The aqueous layer was extracted withdichloromethane (2×15 mL). The combined organic layers were dried overMgSO₄, filtered, and concentrated to afford1-[3-(1-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)propyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolineas a brown oil (1.57 g, 96%) that contained some dichloromethane.

Part H

An aqueous solution of 3 M HCl (3.0 mL) was added to a solution of1-[3-(1-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)propyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinoline(prepared as described in part G, 3.16 mmol) in methanol (10 mL). Asolid formed and additional methanol (10 mL) was added. The reaction wasstirred at rt for 3 d and the solvent was removed in vacuo. The residuewas dissolved in dichloromethane (40 mL) and saturated aqueous sodiumbicarbonate (30 mL) was added so that the pH=8. The aqueous layer wasextracted with dichloromethane (20 mL). The combined organic layers weredried over MgSO₄, filtered, and concentrated to yield1-{3-[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}cyclohexanol(1.14 g, 98%) as a brown gum.

Part I

To a solution of1-{3-[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}cyclohexanol(1.10 g, 2.99 mmol) in chloroform (15 mL) at rt was added m-CPBA (0.96g, 3.89 mmol) in portions. The reaction was stirred for 1.5 h, then wascooled to 0° C. and concentrated ammonium hydroxide (5 mL) was addedfollowed by portionwise addition of p-toluenesulfonyl chloride (0.630 g,3.29 mmol). The mixture was stirred at 0° C. for 1 h, then was filtered.The filtrate was diluted with dichloromethane (30 mL) and saturatedaqueous sodium bicarbonate (30 mL). The layers were separated and theaqueous layer was extracted with dichloromethane (20 mL). The organiclayers were combined, dried over MgSO₄, filtered, and concentrated toafford an orange solid, which was purified by HPFC (silica gel, elutedwith 0-35% CMA/chloroform). The appropriate fractions were concentratedto afford a tan solid that was crystallized from chloroform/hexanes anddried at 75° C. under vacuum to afford1-{3-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}cyclohexanolas white crystals (600 mg, 53%), mp 175-176° C. Anal. calcd forC₂₂H₃₀N₄O₂: C, 69.08; H, 7.91; N, 14.65. Found: C, 68.94; H, 8.21; N,14.53.

Example 132-(Ethoxymethyl)-1-({4-[2-(methylsulfonyl)ethoxy]piperidin-4-yl}methyl)-1H-imidazo[4,5-c]quinolin-4-amine

Part A

To a solution of tert-butyl4-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}-4-hydroxypiperidine-1-carboxylate(prepared as described in Part E of Example 4, 1.9 g, 4.3 mmol) intetrahydrofuran (17 mL) at rt was added solid NaH (60%, 17 mg, 0.43mmol). After 10 min, methyl vinyl sulfone (0.92 g, 8.6 mmol) was addeddropwise. After 1 h, the reaction was quenched with water (50 mL) andextracted with ethyl acetate (50 mL). The organic layer was concentratedunder reduced pressure to afford a yellow oil. Purification by flashchromatography (silica gel, eluted with 5% methanol/dichloromethane)yielded tert-butyl4-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}-4-[2-(methylsulfonyl)ethoxy]piperidine-1-carboxylate(0.40 g, 19%).

Part B

To a solution of4-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}-4-[2-(methylsulfonyl)ethoxy]piperidine-1-carboxylate(0.7 g, 1.28 mmol) in chloroform (13 mL) at rt was addedm-chloroperbenzoic acid (m-CPBA, 0.37 g, 1.28 mmol). After 30 min, thesolution was transferred to a reparatory funnel, diluted with chloroform(50 mL), and washed with saturated aqueous Na₂CO₃ (50 mL). The organiclayer was washed with saturated aqueous Na₂CO₃ (50 mL) and brine (50mL), dried over Na₂SO₄, filtered, and concentrated under reducedpressure to an orange colored oil. To the oil was added dichloromethane(6 mL) and concentrated ammonium hydroxide (2 mL). p-Toluenesulfonylchloride (TsCl, 0.270 g, 1.41 mmol) was added in portions. After 10 min,the reaction mixture was partitioned between chloroform (50 mL) andsaturated aqueous Na₂CO₃. The organic layer was washed with brine (50mL), dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The crude product was purified by flash chromatography (silicagel, eluted with 5% methanol/dichloromethane) to provide tert-butyl4-{[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}-4-[2-(methylsulfonyl)ethoxy]piperidine-1-carboxylateas a white foam (0.40 g, 56%).

Part C

A solution of HCl in ethanol (4.2 M, 0.8 mL, 3.56 mmol) was added to asuspension of tert-butyl4-{[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}-4-[2-(methylsulfonyl)ethoxy]piperidine-1-carboxylate(0.40 g, 0.71 mmol) in ethanol (4 mL) at rt. The resulting yellowsolution was heated at reflux for 1.5 h. The reaction was stirred at rtfor 16 h, then was concentrated under reduced pressure. The resultingsolid was dissolved in water (20 mL) and 20% aqueous NaOH was addeduntil the pH=13. The solution was extracted with dichloromethane (3×50mL). The organic layers were combined, washed with brine (50 mL), driedover Na₂SO₄, filtered, and concentrated under reduced pressure toprovide a solid that was crystallized from acetonitrile. The crystalswere dried under vacuum at 65° C. to provide2-(ethoxymethyl)-1-({4-[2-(methylsulfonyl)ethoxy]piperidin-4-yl}methyl)-1H-imidazo[4,5-c]quinolin-4-amine(0.25 g, 76%) as crystalline plates, mp 212-214° C. ¹H NMR (300 MHz,DMSO-d₆) δ 8.26 (d, J=8.1 Hz, 1H), 7.61 (d, J=8.1 Hz, 1H), 7.44 (t,J=8.1 Hz, 1H), 7.26 (t, J=8.1 Hz, 1H), 6.61 (bs, 2H), 4.85 (s, 2H), 4.81(s, 2H), 3.70 (t, J=5.6 Hz, 2H), 3.55 (q, J=7.5 Hz, 2H), 3.19 (t, J=5.6Hz, 2H), 2.92 (s, 3H) 2.66-2.58 (m, 4H), 1.84 (bs, 1H), 1.70-1.66 (m,2H), 1.48-1.38 (m, 2H), 1.16 (t, J=7.5 Hz, 3H); MS (APCI) m/z 462(M+H)⁺; Anal. Cacld for C₂₂H₃₁N₅O₄S: C, 57.25; H, 6.77; N, 15.17. Found:C, 57.48; H, 7.05; N, 15.57.

Example 141-({1-Acetyl-4-[2-(methylsulfonyl)ethoxy]piperidin-4-yl}methyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinoline-4-amine

Part A

To a solution of tert-butyl4-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}-4-hydroxypiperidine-1-carboxylate(prepared as described in Part E of Example 4, 14.94 g, 33.91 mmol) inethanol (170 mL) was added a solution of HCl in ethanol (2.7 M, 31 mL,84.7 mmol). The solution was heated at reflux for 1 h, during which timea precipitate formed. The mixture was allowed to cool to rt and thevolatiles were removed under reduced pressure. To the residue was addedwater (400 mL) followed by 50% aqueous NaOH until the pH=10. Thesolution was extracted with dichloromethane (3×100 mL). The aqueouslayer was treated with 50% aqueous NaOH until the pH=12, then wasextracted with dichloroemethane (2×100 mL). The organic layers werecombined, dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The resulting solid was triturated with hot ethyl acetate andthe remaining solid was isolated by filtration to afford4-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}piperidin-4-ol(7.0 g, 61%) as an off-white powder.

Part B

Acetyl chloride (0.57 mL, 8.1 mmol) was added to a suspension of4-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}piperidin-4-ol(2.50 g, 7.34 mmol) and triethylamine (1.50 mL, 11.0 mmol) indichloromethane (37 mL) at rt. The resulting solution was stirred for 1h. The solution was diluted with dichloromethane (100 mL) and washedwith water (50 mL) and saturated aqueous sodium bicarbonate (50 mL). Thecombined aqueous layers were back-extracted with dichloromethane (50mL). The combined organic layers were washed with brine (50 mL), driedover Na₂SO₄, filtered, and concentrated under reduced pressure to abrown foam. Purification by flash chromatography (silica gel, elutedwith 10% methanol/dichloromethane) provided1-acetyl-4-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}piperidin-4-olas a white foam (1.8 g, 64%).

Part C

1-Acetyl-4-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}piperidin-4-ol(1.80 g, 4.68 mmol) was converted into1-({1-acetyl-4-[2-(methylsulfonyl)ethoxy]piperidin-4-yl}methyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolineaccording to the method described in Part A of Example 13. Purificationby flash chromatography (silica gel, eluted with 10%methanol/dichloromethane) yielded1-({1-acetyl-4-[2-(methylsulfonyl)ethoxy]piperidin-4-yl}methyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinoline(0.30 g, 13%) and recovered starting material,1-acetyl-4-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}piperidin-4-ol(1.20 g).

Part D

1-({1-Acetyl-4-[2-(methylsulfonyl)ethoxy]piperidin-4-yl}methyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinoline(0.28 g, 0.57 mmol) was converted into1-({1-acetyl-4-[2-(methylsulfonyl)ethoxy]piperidin-4-yl}methyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amineaccording to the method described in Part B of Example 13. Purificationby flash chromatography twice (silica gel, eluted with 10%methanol/dichloromethane) followed by crystallization from acetonitrileyielded1-({1-acetyl-4-[2-(methylsulfonyl)ethoxy]piperidin-4-yl}methyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine(0.10 g, 34%) as crystalline plates, mp 208-210° C. ¹H NMR (300 MHz,DMSO-d₆) δ 8.27 (d, J=8.1 Hz, 1H), 7.61 (d, J=8.1 Hz, 1H), 7.45 (t,J=8.1 Hz, 1H), 7.27 (t, J=8.1 Hz, 1H), 6.62 (bs, 2H), 4.89 (s, 2H), 4.80(s, 2H), 4.12 (d, J=13.8 Hz, 1H), 3.74 (t, J=5.6 Hz, 2H), 3.55 (q, J=6.8Hz, 2H), 3.31 (t, J=5.6 Hz, 2H), 3.24-3.16 (m, 2H), 2.97 (s, 3H) 2.72(t, J=11.8 Hz, 1H), 1.90 (s, 3H), 1.83-1.76 (m, 2H), 1.60-1.44 (m, 2H),1.14 (t, J=6.8 Hz, 3H); MS (APCI) m/z 504 (M+H)⁺; Anal. Cacld forC₂₄H₃₃N₅O₅S: C, 57.24; H, 6.60; N, 13.91. Found: C, 57.08; H, 6.83; N,13.90.

Example 151-{[4-Amino-2-(ethoxymethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclopentanol

A mixture of1-{[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclopentanol(prepared as described in Example 3, 0.50 g, 1.47 mmol) and platinum(IV) oxide (0.25 g) in trifluoroacetic acid (20 mL) was hydrogenated at50 psi (3.5×10⁵ Pa) for 5 d on a Parr apparatus. The reaction mixturewas filtered through CELITE filter agent and the filtrate was treatedwith saturated aqueous NaOH until the pH=14, then was extracted withdichloromethane (3×100 mL). The organic layers were combined, dried overMgSO₄, filtered, and concentrated to an oil that was purified by flashchromatography (silica gel, 10% methanol in dichloromethane). Theappropriate fractions were combined and concentrated to yield acolorless oil. The oil was dissolved in ethanol and 2.7 M HCl in ethanol(1 mL) was added and the mixture was concentrated under reducedpressure. The resulting oil was dissolved in water and Na₂CO₃ was addeduntil the pH=12. A gummy white solid formed and the mixture was heatedat 60° C. for 20 min until a free flowing precipitate formed. Themixture was allowed to cool to rt and the precipitate was isolated byfiltration and dried in a vacuum oven at 80° C. to provide1-{[4-amino-2-(ethoxymethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclopentanolas a white solid, mp 171-173° C. ¹H NMR (300 MHz, DMSO-d₆) δ 5.78 (br s,2H), 4.77 (br s, 2H), 4.66 (s, 1H), 4.45 (br s, 2H), 3.46 (q, J=7.0 Hz,2H), 2.95 (m, 2H), 2.66 (m, 2H), 1.82-1.36 (m, 12H), 1.11 (t, J=7.0 Hz,3H); MS (ESI) m/z 345 (M+H)⁺; Anal. Calcd for C₁₉H₂₈N₄O₂.0.2 H₂O: C,65.57; H, 8.22; N, 16.10. Found: C, 65.78; H, 8.27; N, 15.70.

Examples 16-53

A mixture (50 mL) of the 1.5 hydrate of the dihydrochloride salt of4-[(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]-4-hydroxypiperidine(2.26 g, 5 mmol, prepared in a similar manner as described in Example 5)and anhydrous pyridine was heated until a solution formed. The solutionwas allowed to cool and aliquots (1 mL, 0.1 mmol) were transferred to 50test tubes. Appropriate amounts of the reagents (1.1 equivalents) listedbelow were added to the solutions in the test tubes. The test tubes wereshaken overnight. The solvent was removed from the test tubes by vacuumcentrifugation.

The compounds were purified by preparative high performance liquidchromatography (prep HPLC) using a Waters Fraction Lynx automatedpurification system. The prep HPLC fractions were analyzed using aMicromass LC/TOF-MS, and the appropriate fractions were centrifugeevaporated to provide the trifluoroacetate salt of the desired compound.Column: Zorbax BonusRP, 21.2×50 millimeters (mm), 5 micron particlesize; non-linear gradient elution from 5-95% B where A is 0.05%trifluoroacetic acid/water and B is 0.05% trifluoroaceticacid/acetonitrile; fraction collection by mass-selective triggering. Thetable below shows the reagent used for each example, the structure ofthe resulting compound, and the observed accurate mass for the isolatedtrifluoroacetate salt.

Meas- Ex- ured am- Mass ple Reagent R (M + H) 16 Acetyl chloride

398.2201 17 Methyl chloroformate

414.2140 18 Cyclopropanecarbonyl chloride

424.2343 19 Butyryl chloride

426.2506 20 Cyclobutanecarbonyl chloride

438.2492 21 Benzoyl chloride

460.2353 22 Cyclopentylacetyl chloride

466.2838 23 3-Cyanobenzoyl chloride

485.2313 24 3-Methoxybenzoyl chloride

490.2451 25 3-Chlorobenzoyl chloride

494.1923 26 Nicotinoyl chloride hydrochloride

461.2328 27 trans-2-Phenyl-1- cyclopropanecarbonyl chloride

500.2654 28 4-Acetamidobenzoyl chloride

517.2612 29 Methanesulfonyl chloride

434.1852 30 Ethanesulfonyl chloride

448.2020 31 1-Propanesulfonyl chloride

462.2150 32 Benzenesulfonyl chloride

496.2027 33 1-Methylimidazole-4- sulphonyl chloride

500.2097 34 2- Fluorobenzenesulfonyl chloride

514.1899 35 3- Fluorobenzenesulfonyl chloride

514.1904 36 4- Fluorobenzenesulfonyl chloride

514.1935 37 2- Cyanobenzenesulfonyl chloride

521.1967 38 3- Cyanobenzenesulfonyl chloride

521.1950 39 4- Cyanobenzenesulfonyl chloride

521.2000 40 Methyl isocyanate

413.2282 41 Ethyl isocyanate

427.2455 42 Isopropyl isocyanate

441.2593 43 Isopropyl isothiocycante

457.2386 44 Phenyl isocyanate

475.2425 45 Cyclohexyl isocyanate

481.2922 46 Benzyl isocyanate

489.2624 47 m-Tolyl isocyanate

489.2628 48 3-Methoxyphenyl isocyanate

505.2539 49 3-Chlorophenyl isocyanate

509.2057 50 4-Chlorophenyl isocyanate

509.2052 51 N,N- Dimethylcarbamoyl chloride

427.2438 52 4- Morpholinylcarbonyl chloride

469.2555 53 N-Methyl-N- phenylcarbamoyl chloride

489.2646

Example 54N-(1-{[4-Amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexyl)acetamide

Part A

Sodium cyanide (23.7 g, 482 mmol) was added to a solution of ammoniumhydroxide (28%, 122 mL, 965 mmol) and ammonium chloride (28.4 mL, 531mmol) in water (100 mL). Cyclohexanone (50 mL, 482 mmol) was added over5 min. The reaction was heated at 60° C. for 6 h, then was allowed tocool to rt and stir overnight. The mixture was transferred to aseparatory funnel and was washed with dichloromethane (3×200 mL). Theorganic layers were combined, dried over MgSO₄, filtered, andconcentrated under reduced pressure. Purification by flashchromatography (silica gel, eluted with 20% hexanes/ethyl acetate)provided 1-aminocyclohexanecarbonitrile as a clear oil (49.5 g, 83%).

Part B

A mixture of 1-aminocyclohexanecarbonitrile (48.5 g, 391 mmol) andplatinum oxide (5.0 g) in 4.2 M HCl in ethanol (200 mL) and 2.7 M HCl inethanol (300 mL) was hydrogenated at 50 psi (3.4×10⁵ Pa) for 20 h on aParr apparatus. The reaction mixture was filtered through CELITE filteragent and the filtrate was concentrated to yield a clear oil. The oilwas triturated with isopropanol to yield a white solid that was isolatedby filtration, washed with ether, and dried to provide1-(aminomethyl)cyclohexanamine dihydrochloride (70.0 g, 89%).

Part C

To a 0° C. solution of 4-chloro-3-nitroquinoline (25.0 g, 120 mmol) andtriethylamine (84 mL, 599 mmol) in dichloromethane (500 mL) was added1-(aminomethyl)cyclohexanamine dihydrochloride (36.2 g, 180 mmol). Thereaction was allowed to warm to rt and stirred for 20 h. The reactionwas transferred to a separatory funnel and washed with water (200 mL).The water was back-extracted with dichloromethane (2×500 mL). Theorganic layers were combined, dried over Na₂SO₄, filtered, andconcentrated under reduced pressure to yieldN-[(1-aminocyclohexyl)methyl]-3-nitroquinolin-4-amine as a yellow solid(35.5 g, 99%).

Part D

To a 0° C. solution ofN-[(1-aminocyclohexyl)methyl]-3-nitroquinolin-4-amine (38.0 g, 127 mmol)in tetrahydrofuran (250 mL) was added dropwise 2 M aqueous NaOH (64 mL,128 mmol). A solution of di-tert-butyl dicarbonate (27.6 g, 127 mmol) intetrahydrofuran (150 mL) was added to the reaction mixture over 60 min.The reaction was allowed to warm to rt. After 3 d, additionaldi-tert-butyl dicarbonate (10 g) was added to the reaction. The solventwas removed under reduced pressure and the resulting orange oil wasdissolved in dichloromethane (1 L) and washed with water (3×500 mL). Thecombined aqueous layers were back-extracted with dichloromethane (500mL). The organic layers were combined, dried over MgSO₄, filtered, andconcentrated under reduced pressure to yield an orange oil. Purificationby flash chromatography (silica gel, eluted with 30% ethylacetate/hexanes) provided tert-butyl1-{[(3-nitroquinolin-4-yl)amino]methyl}cyclohexylcarbamate as a yellowsolid (29.8 g, 59%).

Part E

A mixture of tert-butyl1-{[(3-nitroquinolin-4-yl)amino]methyl}cyclohexylcarbamate (29.5 g, 73.7mmol) and 5% platinum on carbon (0.30 g) in toluene (300 mL) washydrogenated at 50 psi (3.5×10⁵ Pa) for 4 hours (h) on a Parr apparatus.The reaction mixture was diluted with ethanol (200 mL) and was filteredthrough CELITE filter agent. The filtrate was concentrated to givetert-butyl 1-{[(3-aminoquinolin-4-yl)amino]methyl}cyclohexylcarbamate asa brown solid (27.3 g, 100%).

Part F

Ethoxyacetyl chloride (9.00 g, 73.4 mmol) was reacted with tert-butyl1-{[(3-aminoquinolin-4-yl)amino]methyl}cyclohexylcarbamate (27.2 g, 73.4mmol) according to the method described in Part E of Example 9 and theresulting product was treated according to the method described in PartE of Example 9. After the solvent was removed to yield an oil, the oilwas dissolved in ethanol (300 mL) and water (30 mL). Sodium hydroxide(4.3 g, 108 mmol) was added and the solution was heated at reflux for 6h. The volatiles were removed under reduced pressure and the resultingbrown oil was partitioned between dichloromethane (500 mL) and water.The organic layer was dried over Na₂SO₄, filtered, and concentratedunder reduced pressure to yield a brown oil. Purification by flashchromatography (silica gel, 30% ethyl acetate/hexanes) providedtert-butyl1-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexylcarbamateas a brown solid (11.9 g, 38%).

Part G

To a solution of tert-butyl1-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexylcarbamate(24.6 g, 56.1 mmol) in ethanol (100 mL) was added 2.7 M HCl in ethanol(150 mL). The solution was heated at 65° C. for 4 h, the was allowed tocool to rt overnight. A light brown precipitate was isolated byfiltration and washed with ethanol. The precipitate was dissolved inwater (100 mL) and NaOH was added until the pH=14. The mixture wasextracted with dichloromethane (3×200 mL). The organic layers werecombined, dried over Na₂SO₄, filtered, and concentrated to an oil thatwas dissolved in ethanol (100 mL). To the ethanol solution was added 2.7M HCl in ethanol (18.7 mL). A pale tan solid crashed out of solution andwas isolated by filtration and dried. The solid was dissolved in water(100 mL) and NaOH was added until the pH=14. The mixture was extractedwith dichloromethane (3×200 mL). The organic layers were combined, driedover Na₂SO₄, filtered, and concentrated to yield1-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexanamineas a light yellow oil (15.1 g, 79%).

Part H

Acetyl chloride (0.036 mL, 0.50 mmol) was added to a 0° C. solution of1-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexanamine(0.17 g, 0.50 mmol) and triethylamine (0.11 mL, 0.75 mmol) indichloromethane (5 mL). The solution was stirred at 0 C for 2 h, then atrt for 1 h. The reaction was repeated on a larger scale with1-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexanamine(2.00 g, 5.91 mmol). The reactions were combined and washed with water(100 mL). The organic phase was dried over Na₂SO₄, filtered, andconcentrated under reduced pressure to yield a light yellow oil.Purification by flash chromatography (silica gel, 15% methanol/ethylacetate) affordedN-(1-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexyl)acetamideas a white oil (2.20 g, 90%).

Part I

N-(1-{[2-(Ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexyl)acetamide(2.0 g, 5.26 mmol) was converted toN-(1-{[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexyl)acetamidefollowing the method described in part F of Example 9. The final productwas crystallized from ethyl acetate/hexanes to affordN-(1-{[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexyl)acetamide(0.52 g, 25%) as light tan crystals, mp 178-180° C. ¹H NMR (300 MHz,CDCl₃) δ 8.29 (dd, J=8.3, 1.0 Hz, 1H), 7.80 (dd, J=8.4, 0.9 Hz, 1H),7.51 (ddd, J=8.3, 7.0, 1.3 Hz, 1H), 7.32 (ddd, J=8.3, 6.9, 1.4 Hz, 1H),5.46 (br s, 2H), 5.19 (br s, 1H), 5.07 (br s, 2H), 4.83 (br s, 2H), 3.62(m, 2H), 2.39 (br s, 2H), 1.94 (s, 3H), 1.65-1.44 (m, 3H), 1.39-0.95 (m,8H); MS (ESI) m/z 396 (M+H)⁺; Anal. Calcd for C₂₂H₂₉N₅O₂.0.25 H₂O: C,66.06; H, 7.43; N, 17.51. Found: C, 65.73; H, 7.61; N, 17.48.

Example 55N-(1-{[4-Amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexyl)methanesulfonamide

Part A

Methanesulfonyl chloride (0.75 mL, 9.75 mmol) was added to a 0° C.solution of1-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexanamine(2.75 g, 8.13 mmol), 4-dimethylaminopyridine (DMAP, 2.75 g) and pyridine(11 mL) in dichloromethane (28 mL). The solution was stirred at 0° C.for 2 h, then at rt for 1 h. The reaction was washed with water (100mL). The organic phase was dried over Na₂SO₄, filtered, and concentratedunder reduced pressure to yield a light yellow oil. Purification byflash chromatography (silica gel, 20% methanol/ethyl acetate) affordedN-(1-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexyl)methanesulfonamideas a white solid (2.72 g, 80%).

Part B

N-(1-{[2-(Ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexyl)methanesulfonamide(2.60 g, 6.24 mmol) was converted intoN-(1-{[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexyl)methanesulfonamideusing the method described in Part F of Example 10. The crudeN-(1-{[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexyl)methanesulfonamidewas purified by flash chromatography twice (silica gel, eluted with 20%methanol/ethyl acetate for the first column, and 15%methanol/dichloromethane for the second column) then crystallized fromacetonitrile to afford white crystals (1.3 g, 48%), mp 186-188° C. ¹HNMR (300 MHz, DMSO-d₆) δ 8.39 (m, 1H), 7.61 (dd, J=8.3, 1.4 Hz, 1H),7.42 (ddd, J=8.3, 7.0, 1.3 Hz, 1H), 7.21 (ddd, J=8.3, 7.1, 1.4 Hz, 1H),7.03 (br s, 1H), 6.45 (br s, 2H), 5.05 (br s, 2H), 4.84 (br s, 2H), 3.56(q, J=7.0 Hz, 2H), 3.14 (s, 3H), 2.22-2.07 (m, 2H), 1.64-1.26 (m, 5H),1.18-1.00 (m, 2H), 1.15 (t, J=7.0 Hz, 3H), 0.90-0.69 (m, 1H); MS (APCI)m/z 432 (M+H)⁺; Anal. Calcd for C₂₁H₂₉N₅O₃S: C, 58.45; H, 6.77; N,16.23. Found: C, 58.34; H, 6.80; N, 16.19.

Example 56N-(1-{[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexyl)-N-isopropylurea

Part A

Isopropyl isocyanate (0.15 mL, 1.45 mmol) was added to a solution of1-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexanamine(0.50 g, 1.45 mmol) dichloromethane (5 mL) at rt. After 4 h, thereaction was set up on a larger scale with1-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexanamine(1.50 g, 4.43 mmol). Both reactions were allowed to stir overnight andadditional isopropyl isocyanate (0.5 equivalent) was added to eachreaction. After stirring another day, the reactions were combined andconcentrated under reduced pressure to yield an oil. The oil wastriturated with hexane andN-(1-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexyl)-N-isopropylureawas isolated as a white solid (2.23 g, 89%).

Part B

N-(1-{[2-(Ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexyl)-N-isopropylurea(2.20 g, 5.19 mmol) was converted toN-(1-{[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexyl)-N-isopropylureafollowing the method described in part F of Example 9. The crude finalproduct was purified by flash chromatography (silica gel, eluted with20% methanol/ethyl acetate) to provide a tan oil. The oil was trituratedwith ethyl acetate/hexanes to provide a white powder that was isolatedby filtration. The white powder was purified by flash chromatographyagain (silica gel, 10% methanol/dichloromethane). The resulting oil wasdissolved in ethanol (20 mL) and 1 M HCl in ethanol (1 mL) was added.After thirty minutes, the volatiles were removed under reduced pressureand the residue was dissolved in water (100 mL). Solid Na₂CO₃ was addedto the solution until a precipitate formed. The solid was isolated byfiltration, washed with water, and dried in a vacuum oven at 80° C. toprovideN-(1-{[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexyl)-N-isopropylureaas a white solid (0.40 g, 18%), mp 135-160° C. ¹H NMR (300 MHz, CDCl₃) δ8.24 (m, 1H), 7.78 (m, 1H), 7.47 (m, 1H), 7.29 (m, 1H), 5.37 (br s, 2H),5.03 (s, 2H), 4.83 (br s, 2H), 4.24 (br d, J=6.9 Hz, 1H), 4.00 (s, 1H),3.85-3.74 (m, 1H), 3.64 (q, J=7.0 Hz, 2H), 1.72-0.96 (m, 10H), 1.23 (t,J=7.0 Hz, 3H), 1.14 (d, J=6.6 Hz, 6H); MS (APCI) m/z 439 (M+H)⁺; Anal.Calcd for C₂₄H₃₄N₆O₂.0.60 H₂O: C, 64.15; H, 7.90; N, 18.70. Found: C,64.05; H, 7.77; N, 18.63.

Example 571-[(4-Amino-2-propyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]cyclohexanol

Part A

Triethylamine (8.38 mL, 60.1 mmol) was added over 10 min to a stirredmixture of 4-chloro-3-nitro-1,5-naphthyridine (6.00 g, 28.6 mmol) and1-aminomethyl-1-cyclohexanol hydrochloride (5.00 g, 30.1 mmol) indichloromethane (115 mL) at 0° C. The solution was allowed to warm to rtand more 1-aminomethyl-1-cyclohexanol hydrochloride (0.2 g) was added.The solution was stirred overnight and more triethylamine (0.5 mL) wasadded. After 30 min, the solution was partitioned between saturatedaqueous sodium bicarbonate (100 mL) and chloroform (200 mL). The aqueouslayer was extracted with chloroform (3×200 mL). The combined organicextracts were washed with saturated aqueous sodium bicarbonate (2×100mL) and brine (80 mL), dried over MgSO₄, filtered, concentrated underreduced pressure, and dried under vacuum to afford1-{[(3-nitro[1,5]naphthyridin-4-yl)amino]methyl}cyclohexanol as a yellowsolid (8.65 g, 100%).

Part B

A mixture of1-{[(3-nitro[1,5]naphthyridin-4-yl)amino]methyl}cyclohexanol (4.55 g,15.1 mmol) and 5% platinum on carbon (0.50 g) in acetonitrile (100 mL)was hydrogenated at 50 psi (3.5×10⁵ Pa) overnight on a Parr apparatus.The reaction mixture was filtered through CELITE filter agent, which wasrinsed with methanol afterwards. The filtrate was concentrated to give1-{[(3-amino[1,5]naphthyridin-4-yl)amino]methyl}cyclohexanol. The1-{[(3-amino[1,5]naphthyridin-4-yl)amino]methyl}cyclohexanol wasconcentrated from chloroform several times to remove residual methanoland was used directly onto the next step.

Part C

A solution of1-{[(3-amino[1,5]naphthyridin-4-yl)amino]methyl}cyclohexanol (preparedas described in Part B, 15.1 mmol), trimethyl orthobutyrate (2.63 mL,16.6 mmol), and pyridine hydrochloride (0.650 g, 5.64 mmol) in toluene(100 mL) was heated at reflux overnight. The solution was allowed tocool to rt, then was concentrated under reduced pressure. The residuewas partitioned between chloroform (200 mL) and saturated aqueous sodiumbicarbonate (75 mL). The aqueous layer was extracted with chloroform(2×50 mL). The combined organic layers were washed with brine (50 mL),dried over MgSO₄, filtered, and concentrated under reduced pressure. Theresulting solid was triturated with ethyl acetate and isolated byfiltration. The filtrate was concentrated and the solid was againtriturated with ethyl acetate; this procedure was repeated two moretimes. The white solids were combined and dried under vacuum to yield1-[(2-propyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]cyclohexanol(3.40 g, 70% over two steps).

Part D

To a solution of1-[(2-propyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]cyclohexanol(1.43 g, 4.41 mmol) in chloroform (20 mL) at rt was addedm-chloroperbenzoic acid (m-CPBA, 70%, 2.17 g, 8.82 mmol). After 1.5 h,the solution was was cooled to 0° C. and concentrated ammonium hydroxide(5 mL) was added. After 3 min, p-toluenesulfonyl chloride (TsCl, 0.920g, 4.85 mmol) was added in portions. After 1 h, the reaction mixture wasfiltered and the filter cake was washed with chloroform. The filtratewas washed with saturated aqueous sodium bicarbonate (50 mL) and driedover Na₂SO₄, filtered, and concentrated under reduced pressure to yieldan orange foam which was purified twice by HPFC (silica gel, gradientelution with 0-25% CMA/CHCl₃ where CMA is a solution comprised of 80%CHCl₃, 18% MeOH, and 2% conc. NH₄OH; followed by 0-30% CMA/CHCl₃). Theappropriate fractions were concentrated and triturated withacetonitrile. The solid was isolated by filtration and dried at 100° C.under vacuum to yield1-[(4-amino-2-propyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]cyclohexanol(567 mg, 38%) as a white powder, mp 209.0-211.0° C. Anal. Calcd forC₁₉H₂₅N₅O.0.2H₂O C, 66.35; H, 7.47; N, 20.36. Found: C, 66.62; H, 7.34;N, 20.05.

Example 581-{[4-Amino-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]methyl}cyclohexanol

Part A

Ethoxyacetyl chloride (1.78 g, 14.6 mmol) was added dropwise to a 0° C.solution of 1-{[(3-amino[1,5]naphthyridin-4-yl)amino]methyl}cyclohexanol(prepared as described in Part B of Example 57, 13.2 mmol) indichloromethane (90 mL). After 1.5 h, more ethoxyacetyl chloride (0.3mL) was added and stirring was continued for another 30 min. Moreethoxyacetyl chloride (0.4 mL) was added and stirring was continuedovernight. The solvent was removed under reduced pressure and theresidue was dissolved in ethanol (90 mL). Sodium hydroxide (1.06 g, 26.5mmol) was added and the reaction was heated at reflux for about 1 d. Thesolvent was removed under reduced pressure and the residue waspartitioned between dichloromethane (200 mL) and water (100 mL). Theaqueous phase was extracted with dichloromethane (2×100 mL). Thecombined organic layers were washed with brine (50 mL), dried overMgSO₄, filtered, and concentrated under reduced pressure to yield abrown foam. The foam was triturated with ethyl acetate and sonicatedbriefly. A white solid was isolated by filtration. The filtrate wasconcentrated and the trituration process was repeated two more times.The off white solids were combined and dried to yield1-{[2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]methyl}cyclohexanol(3.40 g, 76% over three steps).

Part B

1-{[2-(Ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]methyl}cyclohexanol(1.50 g, 4.41 mmol) was converted to1-{[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]-1,5-naphthyridin-1-yl]methyl}cyclohexanolaccording to the method described in Part D of Example 57. The finalproduct was purified by HPFC twice (silica gel, gradient elution with0-30% CMA/CHCl₃). The appropriate fractions were concentrated andtriturated with acetonitrile. The solid was isolated by filtration,recrystallized twice from dichloromethane/hexanes and dried at 100° C.under vacuum to yield1-{[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]methyl}cyclohexanol(350 mg, 22%) as a white powder, mp 171.0-173.0° C. Anal. Calcd forC₁₉H₂₅N₅O₂ C, 64.20; H, 7.09; N, 19.70. Found: C, 63.91; H, 7.40; N,19.67.

Example 591-[(4-Amino-6,7-dimethyl-2-propyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl]cyclohexanol

Part A

A 500 mL round bottom flask was charged with2,4-dichloro-5,6-dimethyl-3-nitropyridine (6.00 g, 27.1 mmol),1-aminomethyl-1-cyclohexanol hydrochloride (4.94 g, 29.8 mmol), andN,N-dimethylformamide (200 mL). The solution was cooled to 0° C. andtriethylamine (8.31 mL, 59.6 mmol) was added dropwise. The solution washeated to 35° C. for 3 d. The volatiles were removed under reducedpressure and the resulting oil was partitioned between dichloromethane(300 mL) and water (50 mL). The organic layer was washed with water (50mL) and brine (30 mL), dried over MgSO₄, filtered, concentrated underreduced pressure, and dried under vacuum to yield1-{[(2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)amino]methyl}cyclohexanolthat was used without further manipulation in the next step.

Part B

A solution of1-{[(2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)amino]methyl}cyclohexanol(prepared as described in Part A, 27.1 mmol), dibenzylamine (15.6 mL,81.3 mmol), and triethylamine (5.67 mL, 40.7 mmol) in toluene (100 mL)was heated at reflux for 7 d. The volatiles were removed under reducedpressure and the residue was partitioned between chloroform (300 mL) andwater (100 mL). The aqueous layer was extracted with chloroform (2×75mL). The combined organic layers were washed with brine (50 mL), driedover MgSO₄, filtered, and concentrated to give a semi-solid. Thesemi-solid was triturated with 1:2 ethyl acetate/hexanes and filtered.The filtrate was concentrated to an orange oil that was purified on aBiotage (gradient elution, 0-30% ethyl acetate/hexanes) to yield an oilcontained both product and dibenzylamine. The oil was dissolved in ethylacetate (100 mL) and 1 M HCl in diethyl ether (50 mL) and methanol (100mL) were added. The solution was stirred for 10 minutes and the solventwas removed in vacuo. The residue was triturated with 1:2 ethylacetate/hexanes and filtered. The filtrate was concentrated, and theresulting oil was dissolved in chloroform (300 mL), washed withsaturated aqueous sodium bicarbonate (50 mL), dried over MgSO₄,filtered, and concentrated. The material was dissolved in ethyl acetate(400 mL) and washed with 10% aqueous citric acid (2×100 mL), saturatedaqueous sodium bicarbonate (50 mL) and brine (50 mL), dried over MgSO₄,filtered, and concentrated in vacuo to yield1-({[2-(dibenzylamino)-5,6-dimethyl-3-nitropyridin-4-yl]amino}methyl)cyclohexanol(10.14 g, 79% yield over two steps).

Part C

A mixture of1-({[2-(dibenzylamino)-5,6-dimethyl-3-nitropyridin-4-yl]amino}methyl)cyclohexanol(4.00 g, 8.43 mmol) and 5% platinum on carbon (0.40 g) in ethyl acetate(84 mL) was hydrogenated at 50 psi (3.4×10⁵ Pa) for 3 h on a Parrapparatus. The reaction mixture was filtered through CELITE filteragent, which was rinsed with ethyl acetate afterwards. The filtrate wasconcentrated to give1-({[3-amino-2-(dibenzylamino)-5,6-dimethylpyridin-4-yl]amino}methyl)cyclohexanoland was used directly in the next step.

Part D

1-({[3-amino-2-(dibenzylamino)-5,6-dimethylpyridin-4-yl]amino}methyl)cyclohexanol(prepared as described in Part C, 8.43 mmol) was converted to1-{[4-(dibenzylamino)-6,7-dimethyl-2-propyl-1H-imidazo[4,5-c]pyridin-1-yl]methyl}cyclohexanol(4.08 g, 97%) according to the method described in Part C of Example 57.

Part E

A mixture of1-{[4-(dibenzylamino)-6,7-dimethyl-2-propyl-1H-imidazo[4,5-c]pyridin-1-yl]methyl}cyclohexanol(1.50 g, 3.02 mmol), ammonium formate (2.84 g, 45.0 mmol), and 10%palladium on carbon (1.50 g) in methanol (60 mL) and ethanol (120 mL)was heated at 85° C. for 2 h. More ammonium formate (1.00 g) was addedand heating was continued of 3 h, then the reaction mixture was stirredovernight at rt. The mixture was filtered through CELITE filter agentand the filtrate was concentrated in vacuo. The crude product waspurified using HPFC (gradient elution with 10-40% CMA/chloroform). Theappropriate fractions were concentrated and the resulting solid wastriturated with acetonitrile. A solid was isolated by filtration anddried at 100° C. under vacuum to provide1-[(4-amino-6,7-dimethyl-2-propyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl]cyclohexanolas a white powder (0.61 g, 64%), mp 214.0-216.0° C. Anal. Calcd forC₁₈H₂₈N₄O C, 68.32; H, 8.92; N, 17.71. Found: C, 68.06; H, 8.65; N,17.45.

Example 604-{[4-Amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}tetrahydro-2H-pyran-4-ol

Part A

4-{[2-(2-Methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}tetrahydro-2H-pyran-4-olwas prepared according to the general methods of Example 10 usingmethoxypropionyl chloride in lieu of ethoxyacetyl chloride in Part E.

Part B

4-{[2-(2-Methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}tetrahydro-2H-pyran-4-ol(2.97 g) was oxidized and then aminated according to the method of PartI of Example 12 except that the amination was run at ambienttemperature. The crude product was purified by HPFC eluting with agradient of 0 to 45% CMA in chloroform to provide a yellow solid. Thesolid was triturated with acetonitrile, isolated by filtration, anddried in a vacuum oven at 85° C. to provide4-{[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}tetrahydro-2H-pyran-4-olas a tan solid, mp 205-206° C. MS (ESI) m/z 357 (M+H)⁺; Anal. calcd forC₁₉H₂₄N₄O₃: C, 64.03; H, 6.79; N, 15.72. Found: C, 63.93; H, 6.79; N,15.61.

Example 614-{[4-Amino-2-(2-hydroxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}tetrahydro-2H-pyran-4-ol

A suspension of4-{[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}tetrahydro-2H-pyran-4-ol(0.95 g, 2.67 mmol) in dichloromethane (15 mL) was cooled to 0° C. Borontribromide (8 mL, 8.00 mmol) was added and the reaction mixture wasallowed to stir overnight while slowly warming to ambient temperature.The reaction mixture was concentrated. The residue was taken up in amixture of methanol (15 mL) and 6M hydrochloric acid (10 mL) andrefluxed for 2.5 hours. The reaction mixture was cooled to ambienttemperature and the pH was adjusted to 8 with 2M sodium hydroxide. Themixture was extracted with chloroform (12×20 mL). The combined extractswere dried over magnesium sulfate, filtered, and then concentrated underreduced pressure to provide a yellow solid. This material purified byHPFC eluting with a gradient of 0 to 45% CMA in chloroform to provide anoff white solid. The solid was triturated with acetonitrile, isolated byfiltration, and dried in a vacuum oven at 140° C. to provide 0.536 g of4-{[4-amino-2-(2-hydroxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}tetrahydro-2H-pyran-4-olas a white solid, mp 237-238° C. MS (ESI) m/z 343 (M+H)⁺; Anal. calcdfor C₁₈H₂₂N₄O₃: C, 63.14; H, 6.48; N, 16.36. Found: C, 63.04; H, 6.57;N, 16.19.

Example 624-{[4-Amino-2-(hydroxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}tetrahydro-2H-pyran-4-ol

Part A

4-[(2-Chloromethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]tetrahydro-2H-pyran-4-olwas prepared according to the general methods of Example 10 usingchloroacetyl chloride in lieu of ethoxyacetyl chloride in Part E.

Part B

3-Chloroperbenzoic acid (0.46 g) was added to a solution of4-[(2-chloromethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]tetrahydro-2H-pyran-4-ol(0.44 g) in chloroform (8 mL) and the reaction mixture was stirred atambient temperature for 2 hours. The reaction mixture was diluted withaqueous saturated sodium bicarbonate (30 mL) and stirred for 20 minutes.4-[(2-chloromethyl-5-oxy-1H-imidazo[4,5-c]quinolin-1-yl)methyl]tetrahydro-2H-pyran-4-olwas isolated by filtration as a white solid.

Part C

Benzenesulfonyl chloride (0.36 mL) was added dropwise to a suspension ofthe material from Part B in methanol (8 mL) and ammonium hydroxide (0.44mL). The reaction mixture was stirred at ambient temperature and thenfiltered to provide4-[(4-amino-2-chloromethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]tetrahydro-2H-pyran-4-olhydrochloride as a white solid.

Part D

Potassium acetate (0.08 g) was added to a solution of material from PartC (0.25 g) in N,N-dimethylformamide (4 mL). The reaction mixture wasstirred overnight. Additional potassium acetate (0.08 g) was added andthe reaction mixture was stirred overnight. The solvent was removedunder vacuum to provide4-[(4-amino-2-hydroxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]tetrahydro-2H-pyran-4-olacetate hydrochloride.

Part E

Potassium carbonate (0.36 g) was added to a solution of the materialfrom Part D in methanol (8 mL). The reaction mixture was stirred for 1hour and then concentrated under reduced pressure. The residue wasdiluted with water and then extracted with chloroform (20×10 mL). Thecombined extracts were dried over magnesium sulfate, filtered, and thenconcentrated under reduced pressure to provide a white solid. The solidwas triturated with acetonitrile, isolated by filtration, and dried in avacuum oven at 85° C. to provide 71 mg of4-{[4-amino-2-(hydroxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}tetrahydro-2H-pyran-4-olas a white solid, mp greater than 250° C. MS (ESI) m/z 329 (M+H)⁺; Anal.calcd for C₁₇H₂₀N₄O₃: C, 62.18; H, 6.14; N, 17.06. Found: C, 61.97; H,6.02; N, 17.00.

Example 634-[(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]tetrahydro-2H-pyran-4-ol

Part A

Trimethylorthovalerate (1.8 mL, 10.4 mmol) and pyridine hydrochloride(92 mg, 0.8 mmol) were added to a suspension of4-[(3-aminoquinolin-4-ylamino)methyl]tetrahydropyran-4-ol (8.0 mmol) intoluene (40 mL). The reaction mixture was heated at reflux for 2.5 hoursand then cooled to ambient temperature. A precipitate was isolated byfiltration and dried to provide4-[(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]tetrahydro-2H-pyran-4-olas a white solid, mp 180-181° C. MS (ESI) m/z 340 (M+H)⁺; Anal. calcdfor C₂₀H₂₅N₃O₂: C, 70.77; H, 7.42; N, 12.38. Found: C, 70.58; H, 7.53;N, 12.40.

Part B

The material from Part A was oxidized and then aminated according to themethod of Part I of Example 12 except that the amination was run atambient temperature. The crude product was triturated with hot ethanolto provide 0.822 g of4-[(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]tetrahydro-2H-pyran-4-olas a white solid, mp 235-236° C. MS (ESI) m/z 355 (M+H)⁺; Anal. calcdfor C₂₀H₂₆N₄O₂: C, 67.77; H, 7.39; N, 15.81. Found: C, 67.57; H, 7.49;N, 15.84.

Example 644-[(4-Amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]tetrahydro-2H-pyran-4-ol

Part A

Trimethylorthobutyrate (1.9 mL, 12.0 mmol) and pyridine hydrochloride(58 mg, 0.5 mmol) were added to a suspension of4-[(3-aminoquinolin-4-ylamino)methyl]tetrahydropyran-4-ol (10.0 mmol) intoluene (50 mL). The reaction mixture was heated at reflux for 4 hoursand then concentrated under reduced pressure. The residue was trituratedwith acetonitrile and the filtered to provide4-[(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]tetrahydro-2H-pyran-4-olas a tan solid.

Part B

The material from Part A was oxidized and then aminated according to themethod of Part I of Example 12 except that the amination was run atambient temperature. The crude product was triturated with hot ethanolto provide 0.758 g of4-[(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]tetrahydro-2H-pyran-4-olas a white solid, mp 231-233° C. MS (ESI) m/z 341 (M+H)⁺; Anal. calcdfor C₁₉H₂₄N₄O₂: C, 67.04; H, 7.11; N, 16.46. Found: C, 66.85; H, 7.39;N, 16.42.

Example 654-[(4-Amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]tetrahydro-2H-pyran-4-ol

Part A

Triethylorthopropionate (2.4 mL, 12.0 mmol) and pyridine hydrochloride(60 mg, 0.5 mmol) were added to a suspension of4-[(3-aminoquinolin-4-ylamino)methyl]tetrahydropyran-4-ol (10.0 mmol) intoluene (50 mL). The reaction mixture was heated at reflux for 2.5 hoursand then concentrated under reduced pressure. The residue was trituratedwith acetonitrile and the filtered to provide4-[(2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]tetrahydro-2H-pyran-4-olas a tan solid.

Part B

The material from Part A was oxidized and then aminated according to themethod of Part I of Example 12 except that the amination was run atambient temperature. The crude product was triturated with 1M sodiumhydroxide, isolated by filtration, washed with water, and dried undervacuum at 85° C. to provide 1.6 g of4-[(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]tetrahydro-2H-pyran-4-olas a tan solid, mp greater than 250° C. MS (ESI) m/z 327 (M+H)⁺; Anal.calcd for C₁₈H₂₂N₄O₂: C, 66.24; H, 6.79; N, 17.17. Found: C, 65.99; H,7.08; N, 17.23.

Example 664-[(4-Amino-2-ethoxymethyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]tetrahydro-2H-pyran-4-ol

Part A

A solution of 4-chloro-3-nitro[1,5]naphthyridine (16.6 g, 79.0 mmol) indichloromethane (250 mL) and triethylamine (14.3 mL, 102.7 mmol) wascooled to 4° C. A solution of 4-aminomethyltetrahydropyran-4-ol (11.4 g,86.9 mmol) in dichloromethane (70 mL) was added dropwise over a periodof 30 minutes. The reaction mixture was allowed to stir at ambienttemperature over the weekend and then it was concentrated under reducedpressure. The residue was stirred with water (300 mL). The resultingsolid was isolated by filtration, rinsed with water, and dried in avacuum oven at 50° C. for 4 hours to provide 22.53 g of4-[(3-nitro[1,5]naphthyridin-4-ylamino)methyl]tetrahydropyran-4-ol.

Part B

A mixture of4-[(3-nitro[1,5]naphthyridin-4-ylamino)methyl]tetrahydropyran-4-ol (12.2g), 5% platinum on carbon (1.22 g), and ethyl acetate (160 mL) wasplaced under hydrogen pressure (40 psi, 2.8×10⁵ Pa) for 3 hours. Thereaction mixture was filtered through a layer of CELITE filter aid andthe filter cake was rinsed with 1:1 ethyl acetate:methanol (150 mL). Thefiltrate was concentrated under reduced pressure to provide 12.66 g of4-[(3-amino[1,5]naphthyridin-4-ylamino)methyl]tetrahydropyran-4-ol as athick semi-solid.

Part C

Ethoxyacetyl chloride (1.1 mL, 11.0 mmol) was added dropwise over aperiod of 5 minutes to a chilled (0° C.) suspension of material fromPart B (10.0 mmol) in dichloromethane (50 mL). The reaction mixture wasallowed to warm to ambient temperature and then stirred for two hours.The reaction mixture was concentrated under reduced pressure to provide2-ethoxy-N-{4-[(4-hydroxytetrahydropyran-4-ylmethyl)amino][1,5]napthyridin-3-yl}acetamidehydrochloride as an orange solid.

Part D

Triethylamine (4.2 mL, 30.0 mmol) was added to a solution of thematerial from Part C in ethanol (40 mL). The reaction mixture was heatedat 60° C. overnight and then concentrated under reduced pressure. Theresidue was dissolved in dichloromethane (50 mL) and washed with aqueoussaturated sodium bicarbonate (50 mL). The aqueous layer was backextracted with dichloromethane (2×25 mL). The combined organics weredried over magnesium sulfate, filtered, and then concentrated underreduced pressure to provide a dark yellow oil. This material wascrystallized from acetonitrile to provide 2.96 g of an off white solid.A portion (375 mg) was recrystallized from acetonitrile to provide 281mg of4-{[2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]methyl}tetrahydro-2H-pyran-4-olas white needles, mp 168-169° C. MS (ESI) m/z 343 (M+H)⁺; Anal. calcdfor C₁₈H₂₂N₄O₃: C, 63.14; H, 6.48; N, 16.36. Found: C, 63.06; H, 6.32;N, 16.28.

Part E

Material from Part D (2.92 g) was oxidized and then aminated accordingto the method of Part I of Example 12. The crude product was purified byHPFC eluting with a gradient of 0 to 30% CMA in chloroform to provide atan solid. This material was recrystallized from methanol to provide0.404 g of4-[(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]tetrahydro-2H-pyran-4-olas off-white needles, mp 166-167° C. MS (ESI) m/z 358 (M+H)⁺; Anal.calcd for C₁₈H₂₃N₅O₃: C, 60.49; H, 6.49; N, 19.59. Found: C, 60.43; H,6.45; N, 19.94.

Example 674-[(4-Amino-2-hydroxymethyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]tetrahydro-2H-pyran-4-ol

Boron tribromide (8.4 mL of 1M in dichloromethane) was added dropwiseover a period of 10 minutes to a chilled (0° C.) suspension of4-[(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c]-1,5-naphthyridin-1-yl)methyl]tetrahydro-2H-pyran-4-ol(1.00 g, 2.81 mmol) in dichloromethane (15 mL). The reaction mixture wasallowed to slowly warm to ambient temperature overnight, quenched withmethanol (5 mL), and then concentrated under reduced pressure. Theresidue was dissolved in methanol (15 mL) and 6M hydrochloric acid (10mL). The reaction mixture was heated at reflux for 6 hours, cooled toambient temperature, neutralized with solid sodium bicarbonate and water(15 mL), and then extracted with chloroform (6×15 mL). The combinedorganics were dried over magnesium sulfate, filtered, and thenconcentrated under reduced pressure to provide 0.72 g of a tan solid.This material was purified by HPFC eluting with a gradient of 0 to 50%CMA in chloroform to provide a white solid which was dried under vacuumat 140° C. for 20 hours to provide 0.39 g of4-[(4-amino-2-hydroxymethyl-1H-imidazo[4,5-c]-1,5-naphthyridin-1-yl)methyl]tetrahydro-2H-pyran-4-olas off-white needles, mp greater than 250° C. MS (ESI) m/z 330 (M+H)⁺;Anal. calcd for C₁₆H₁₉N₅O₃: C, 58.35; H, 5.81; N, 21.26. Found: C,58.32; H, 5.81; N, 21.21.

Example 684-{[4-Amino-2-(2-hydroxyethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]methyl}tetrahydro-2H-pyran-4-ol

Part A

4-{[2-(2-Methoxyethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]methyl}tetrahydro-2H-pyran-4-olwas prepared according to the method of Parts A through D of Example 66using 3-methoxypropionyl chloride in lieu of ethoxyacetyl chloride inPart C. The product was provided as white needles, mp 156-157° C. MS(ESI) m/z 343 (M+H)⁺; Anal. calcd for C₁₈H₂₂N₄O₃: C, 63.14; H, 6.48; N,16.36. Found: C, 62.91; H, 6.52; N, 16.53.

Part B

Material from Part A (2.1 g) was oxidized and then aminated according tothe method of Part I of Example 12. The crude product was purified byHPFC eluting with a gradient of 0 to 50% CMA in chloroform to provide apale yellow oil. The oil was triturated with acetonitrile to provide0.83 g of4-{[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]methyl}tetrahydro-2H-pyran-4-olas a tan solid.

Part C

The ether linkage was cleaved according to the method of Example 67. Thecrude product was purified by HPFC eluting with a gradient of 0 to 50%CMA in chloroform to provide a white solid which was dried under vacuumat 140° C. for 20 hours to provide 0.43 g of4-{[4-amino-2-(2-hydroxyethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]methyl}tetrahydro-2H-pyran-4-olas off-white needles, mp 226-227° C. MS (ESI) m/z 344 (M+H)⁺; Anal.calcd for C₁₇H₂₁N₅O₃: C, 59.46; H, 6.16; N, 20.40. Found: C, 59.40; H,6.17; N, 20.35.

Example 694-{[4-Amino-2-(3-hydroxypropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]methyl}tetrahydro-2H-pyran-4-ol

Part A

4-Benzyloxybutyric acid (0.87 mL, 4.93 mmol), 1-hydroxybenzotriazole(0.79 g, 5.83 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide(1.12 g, 5.83 mmol) were added to a solution of4-[(3-amino[1,5]naphthyridin-4-ylamino)methyl]tetrahydropyran-4-ol (1.23g, 4.48 mmol) in DMF (20 mL). The reaction mixture was stirred atambient temperature for 5.5 hours. An additional 0.5 eq ofN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide and1-hydroxybenzotriazole were added and the reaction mixture was stirredovernight. An additional 0.3 eq of the acid was added and the reactionmixture was stirred for an hour. The reaction mixture was combined withthat from another run, diluted with water (100 mL), and extracted withdichloromethane (3×50 mL). The combined organics were washed with brine(75 mL), dried over magnesium sulfate, and then concentrated underreduced pressure to provide 8.03 g of a brown oil. This material waspurified by HPFC eluting with a gradient of 0 to 35% CMA in chloroformto provide 2.67 g of4-benzyloxy-N-4-[(4-hydroxytetrahydropyran-4-ylmethyl)amino][1,5]napthyridin-3-yl}butyramideas a yellow oil.

Part B

The material from Part A was combined with a solution of ammonia inmethanol (25 mL of 7M) and placed in a pressure vessel. The vessel wassealed and then heated at 150° C. for 18 hours. The reaction mixture wascooled and then concentrated under reduced pressure. The residue waspurified by HPFC eluting with a gradient of 0 to 40% CMA in chloroformto provide 1.77 g of4-{[2-(3-benzyloxypropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]methyl}tetrahydro-2H-pyran-4-olas an off white solid.

Part C

The material from Part B was oxidized and then aminated according to themethod of Part I of Example 12. The crude product was purified by HPFCeluting with a gradient of 0 to 40% CMA in chloroform to provide ayellow oil. This material was triturated with acetonitrile to provide0.70 g of4-{[4-amino-2-(3-benzyloxypropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]methyl}tetrahydro-2H-pyran-4-olas a tan solid.

Part D

Acetyl chloride (0.12 mL, 1.64 mmol) and ethanol (10 mL) were combinedat 0° C. and then stirred at ambient temperature for 30 minutes. Thematerial from Part C (1.56 mmol) and 10% palladium on carbon (0.14 g)were added and the mixture was placed under hydrogen pressure (45 psi,3.1×10⁵ Pa) over the weekend. The reaction mixture was filtered througha layer of CELITE filter aid and the filter cake was rinsed withmethanol (30 mL). The filtrate was concentrated under reduced pressure.The residue was combined with aqueous saturated sodium bicarbonate (30mL) and then extracted with chloroform (9×15 mL). The combined organicswere dried over magnesium sulfate, filtered, and then concentrated underreduced pressure to provide a yellow solid. This material was purifiedby HPFC eluting with a gradient of 0 to 50% CMA in chloroform to provide0.36 g of a white solid. This material was triturated with hot methanoland then dried under vacuum at 140° C. to provide 140 mg of4-{[4-amino-2-(3-hydroxypropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]methyl}tetrahydro-2H-pyran-4-olas off-white needles, mp 237-238° C. MS (ESI) m/z 358 (M+H)⁺; Anal.calcd for C₁₈H₂₃N₅O₃: C, 60.49; H, 6.49; N, 19.59. Found: C, 60.56; H,6.48; N, 19.64.

Example 704-[(4-Amino-2-propyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]tetrahydro-2H-pyran-4-ol

Part A

Trimethylorthobutyrate (1.9 mL, 12.0 mmol) and pyridine hydrochloride(23 mg, 0.2 mmol) were added to a suspension of4-[(3-amino[1,5]naphthyridin-4-ylamino)methyl]tetrahydropyran-4-ol (10.0mmol) in toluene (50 mL). The reaction mixture was heated at refluxovernight and then concentrated under reduced pressure. The residue wastriturated with acetonitrile and the resulting solid was isolated byfiltration to provide 2.26 g of4-[(2-propyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]tetrahydro-2H-pyran-4-olas a tan solid.

Part B

The material from Part A was oxidized and aminated according to themethod of Part I of Example 12 except that the amination was run atambient temperature. The crude product was triturated with acetonitrileto provide a yellow solid. This material was recrystallized from hotethanol to provide pale yellow crystals which were triturated with hotacetonitrile and then dried under vacuum at 85° C. to provide 0.546 g of4-[(4-amino-2-propyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]tetrahydro-2H-pyran-4-olas off-white needles, mp 209-210° C. MS (ESI) m/z 342 (M+H)⁺; Anal.calcd for C₁₈H₂₃N₅O₂: C, 63.32; H, 6.79; N, 20.51. Found: C, 63.44; H,6.92; N, 20.65.

Example 714-[(4-Amino-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]tetrahydro-2H-pyran-4-ol

Part A

4-[(1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]tetrahydro-2H-pyran-4-olwas prepared according to the method of Part A of Example 70 usingtrimethylorthoformate in lieu of trimethylorthobutyrate.

Part B

The material from Part A was oxidized and aminated according to themethod of Part I of Example 12 except that the amination was run at 5°C. The crude product was purified by HPFC eluting with a gradient of 0to 35% CMA in chloroform to provide an off white solid. This materialwas triturated with acetonitrile and then dried in a vacuum oven at 85°C. to provide 0.154 g of4-[(4-amino-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]tetrahydro-2H-pyran-4-olas a beige solid, mp 225-226° C. MS (ESI) m/z 300 (M+H)⁺; Anal. calcdfor C₁₅H₁₇N₅O₂: C, 60.19; H, 5.72; N, 23.40. Found: C, 59.97; H, 5.71;N, 23.39.

Example 724-[(4-Amino-2-ethyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]tetrahydro-2H-pyran-4-ol

Part A

4-[(2-ethyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]tetrahydro-2H-pyran-4-olwas prepared according to the method of Part A of Example 70 usingtriethylorthopropionate in lieu of trimethylorthobutyrate.

Part B

The material from Part A was oxidized and aminated according to themethod of Part I of Example 12 except that the amination was run at 5°C. The crude product was triturated sequentially with hot acetonitrileand hot ethanol and then purified by HPFC eluting with a gradient of 0to 30% CMA in chloroform to provide an off white solid. This materialwas triturated with acetonitrile and then dried in a vacuum oven at 85°C. to provide 0.543 g of4-[(4-amino-2-ethyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]tetrahydro-2H-pyran-4-olas off-white needles, mp greater than 250° C. MS (ESI) m/z 328 (M+H)⁺;Anal. calcd for C₁₇H₂₁N₅O₂: C, 62.37; H, 6.47; N, 21.39. Found: C,62.38; H, 6.39; N, 21.53.

Example 731-[3-(4-Amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]cyclohexanol

Part A

Trimethylorthobutyrate (0.86 mL, 5.41 mmol) and pyridine hydrochloride(0.03 g, 0.23 mmol) were added to a solution ofN⁴-{3-[1-tert-butyldimethylsilanyloxy)cyclohexyl]propyl}quinoline-3,4-diamine(4.51 mmol) in toluene (20 mL). The reaction mixture was refluxed for 2hours, cooled to ambient temperature, and then concentrated underreduced pressure. The residue was dissolved in dichloromethane (100 mL)and washed with aqueous saturated sodium bicarbonate (50 mL). Theaqueous was extracted with dichloromethane (2×20 mL). The combinedorganics were dried over magnesium sulfate, filtered, and thenconcentrated under reduced pressure to provide 2.23 g of crude1-{3-[1-tert-butyldimethylsilanyloxy)cyclohexyl]propyl}-2-propyl-1H-imidazo[4,5-c]quinolineas an orange goo.

Part B

The tert-butyldimethylsilyl group was removed according to the method ofPart H of Example 12 to provide1-[3-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]cyclohexanol as abrown solid.

Part C

The material from Part B was oxidized and then aminated according to themethod of Part I of Example 12. The crude product was purified by HPFCeluting with a gradient of 0 to 35% CMA in chloroform to provide a tansolid. This material was recrystallized 3 times from chloroform/hexanesand then dried in a vacuum oven at 75° C. to provide 239 mg of1-[3-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]cyclohexanolas off-white needles, mp 200.5-201.5° C. MS (ESI) m/z 367 (M+H)⁺; Anal.calcd for C₂₂H₃₀N₄O: C, 72.10; H, 8.25; N, 15.29. Found: C, 72.00; H,8.50; N, 15.42.

Example 741-[2-(4-Amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]cyclohexanol

Part A

N⁴-{2-[1-tert-butyldimethylsilanyloxy)cyclohexyl]ethyl}quinoline-3,4-diaminewas prepared according to the general methods of Parts A through G ofExample 12 except that vinyl magnesium bromide was used in lieu of allylmagnesium bromide in Part A and the tert-butyldimethylsilanyl protectinggroup was installed by treating a solution of the cyclohexanol indichloromethane with tert-butyldimethylsilyl trifluoromethanesulfonatein the presence of 2,6-lutidine.

Part B

Trimethylorthoacetate (1.1 mL) and pyridine hydrochloride (42 mg, 0.37mmol) were added to a suspension ofN⁴-{2-[1-tert-butyldimethylsilanyloxy)cyclohexyl]ethyl}quinoline-3,4-diamine(2.95 g, 7.38 mmol) in toluene (30 mL). The reaction mixture wasrefluxed for 2.5 hours, cooled to ambient temperature, and thenconcentrated under reduced pressure. The residue was dissolved indichloromethane (80 mL) and washed with aqueous saturated sodiumbicarbonate (50 mL). The aqueous was extracted with dichloromethane (30mL). The combined organics were dried over magnesium sulfate, filtered,and then concentrated under reduced pressure to provide1-{2-[1-tert-butyldimethylsilanyloxy)cyclohexyl]ethyl}-2-methyl-1H-imidazo[4,5-c]quinolineas a brown solid.

Part C

The tert-butyldimethylsilyl group was removed according to the method ofPart H of Example 12. The crude product was purified by HPFC elutingwith a gradient of 0 to 40% CMA in chloroform to provide 1.70 g of1-[2-(2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]cyclohexanol as atan solid.

Part D

The material from Part C was oxidized and then aminated according to themethod of Part I of Example 12. The crude product was trituratedsequentially with hot methanol and hot ethanol and then dried in avacuum oven at 85° C. to provide 0.549 g of1-[2-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]cyclohexanolas beige needles, mp>252° C. MS (ESI) m/z 325 (M+H)⁺; Anal. calcd forC₁₉H₂₄N₄O.0.02 CHCl₃: C, 69.90; H, 7.41; N, 17.14. Found: C, 69.69; H,7.41; N, 16.95.

Example 751-[2-(4-Amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]cyclohexanol

1-[2-(4-Amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]cyclohexanolwas prepared according to the method of Parts A through D of Example 74using trimethylorthobutyrate in lieu of trimethylorthoacetate in Part B.The crude product was purified by HPFC eluting with a gradient of 0 to40% CMA in chloroform to provide a tan solid. This material wasrecrystallized from hot chloroform and then triturated with hotacetonitrile to provide 0.444 g of pure product as beige needles, mp181-182° C. MS (ESI) m/z 353 (M+H)⁺; Anal. calcd for C₂₁H₂₈N₄O: C,71.56; H, 8.01; N, 15.90. Found: C, 71.37; H, 8.15; N, 15.82.

Example 761-{2-[4-Amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethyl}cyclohexanol

1-{2-[4-Amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethyl}cyclohexanolwas prepared according to the general methods of Parts G through I ofExample 12 usingN-{2-[1-tert-butyldimethylsilanyloxy)cyclohexyl]ethyl}-3-nitroquinolin-4-aminein lieu ofN⁴-{3-[1-tert-butyldimethylsilanyloxy)cyclohexyl]propyl}-3-nitroquinolin-4-aminein Part G. The crude product was purified by HPFC eluting with agradient of 0 to 25% CMA in chloroform to provide a tan solid. Thismaterial was recrystallized from hot chloroform to provide 0.346 g ofpure product as off-white needles, mp 205-206° C. MS (ESI) m/z 369(M+H)⁺; Anal. calcd for C₂₁H₂₈N₄O₂: C, 68.45; H, 7.66; N, 15.20. Found:C, 68.38; H, 7.74; N, 15.13.

Example 77N-({4-Amino-1-[(1-hydroxycyclohexyl)methyl]-1H-imidazo[4,5-c]quinolin-2-yl}methyl)cyclopropanecarboxamide

Part A

Potassium phthalimide (2.59 g, 14.0 mmol) was added to a solution of1-[(4-amino-2-chloromethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]cyclohexanol(13.3 mmol) in DMF (50 mL). The reaction mixture was stirred at ambienttemperature overnight. Additional potassium phthalimide (1.0 g) wasadded. The reaction mixture was stirred for 5 hours and thenconcentrated under reduced pressure. The residue was triturated withmethanol to provide 6.91 g of crude2-({4-amino-1-[(1-hydroxycyclohexyl)methyl]-1H-imidazo[4,5-c]quinolin-2-yl}methyl)isoindole-1,3-dioneas a white solid.

Part B

Hydrazine (2.1 mL, 66.5 mmol) was added to a suspension of the materialfrom Part A in ethanol (50 mL). The reaction mixture was stirred atambient temperature for 24 hours and then concentrated under reducedpressure. The residue was sonicated with 1M hydrochloric acid (50 mL)and then filtered. The filtrate was adjusted to pH 8 with solid sodiumbicarbonate. The resulting precipitate was isolated by filtration anddried in a vacuum oven at 50° C. to provide 2.99 g of1-[(4-amino-2-aminomethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]cyclohexanolas a white powder.

Part C

Triethylamine (0.28 mL, 2.01 mmol) was added to a suspension of materialfrom Part B (0.503 g, 1.55 mmol) in dichloromethane (12 mL). The mixturewas cooled to 0° C. and cyclopropylcarbonyl chloride (0.15 mL, 1.62mmol) was added. The reaction mixture was stirred overnight at ambienttemperature and then diluted with dichloromethane (50 mL) and aqueoussaturated sodium bicarbonate (40 mL). The layers were separated and theaqueous layer was extracted with dichloromethane (2×20 mL). The combinedorganics were dried over magnesium sulfate, filtered, and thenconcentrated under reduced pressure to provide 0.70 g of a white solid.This material was purified by HPFC eluting with a gradient of 0 to 45%CMA in chloroform to provide 0.56 g of a white powder. This material wastriturated with hot acetonitrile, isolated by filtration, and driedunder high vacuum at 100° C. to provide 0.440 g ofN-({4-amino-1-[(1-hydroxycyclohexyl)methyl]-1H-imidazo[4,5-c]quinolin-2-yl}methyl)cyclopropanecarboxamideas white needles, mp is greater than 250° C. MS (ESI) m/z 394 (M+H)⁺;Anal. calcd for C₂₂H₂₇N₅O₂: C, 67.15; H, 6.92; N, 17.80. Found: C,66.93; H, 7.07; N, 17.92.

Example 781-[(4-Amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]cyclohexanol

Part A

A mixture of 1-[(3-nitroquinolin-4-ylamino)methyl]cyclohexanol (10.0 g,33.2 mmol), 5% platinum on carbon (1.0 g), and ethyl acetate (140 mL)was placed under hydrogen pressure (40 psi, 2.8×10⁵ Pa) for 2.5 hours.The reaction mixture was filtered through a layer of CELITE filter aidand the filter cake was rinsed with ethyl acetate (100 mL). The filtratewas concentrated under reduced pressure to provide1-[(3-aminoquinolin-4-ylamino)methyl]cyclohexanol as an orange gooeysolid.

Part B

Trimethylorthoacetate (1.7 mL, 13.2 mmol) was added to a suspension ofmaterial from Part A (11.0 mmol) in toluene (45 mL). The reactionmixture was heated at reflux for 6 hours, allowed to cool to ambienttemperature, and then concentrated under reduced pressure. The residuewas triturated with acetonitrile to provide 2.61 g of1-[(2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]cyclohexanol as a tansolid.

Part C

The material from Part B was oxidized and then animated using the methodof Part I of Example 12 except that the amination was run at ambienttemperature. The crude product was triturated sequentially with 2Msodium hydroxide and hot ethanol to provide 1.00 g of1-[(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]cyclohexanolas beige needles, mp is greater than 250° C. MS (ESI) m/z 311 (M+H)⁺;Anal. calcd for C₁₈H₂₂N₄O: C, 69.65; H, 7.14; N, 18.05. Found: C, 69.64;H, 7.40; N, 18.35.

Example 791-[(4-Amino-1H-imidazo[4,5-c]quinolin-1-yl)methyl]cyclohexanol

1-[(4-Amino-1H-imidazo[4,5-c]quinolin-1-yl)methyl]cyclohexanol wasprepared according to the general methods of Example 78 except thattrimethylorthoformate was used in lieu of trimethylorthoacetate in PartB. The crude product was triturated sequentially with 1M sodiumhydroxide and hot ethanol and then further purified by HPFC eluting witha gradient of 0 to 50% CMA in chloroform to provide an off-white solid.This material was triturated with boiling methanol and then dried in avacuum oven at 130° C. to provide product as off-white needles, mpgreater than 250° C. MS (ESI) m/z 297 (M+H)⁺; Anal. calcd for C₁₇H₂₀N₄O:C, 68.90; H, 6.80; N, 18.90. Found: C, 68.57; H, 6.62; N, 18.75.

Example 801-{[4-Amino-2-(hydroxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexanol

Part A

Ethyl chloroacetimidate hydrochloride (1.90 g, 12.0 mmol) was added to asolution of 1-[(3-aminoquinolin-4-ylamino)methyl]cyclohexanol (10.0mmol) in 1,2-dichloroethane (70 mL) and the reaction mixture was heatedat 65° C. for 8 hours. Additional imidate (1.2 eq) was added and thereaction mixture was heated at 65° C. overnight. Additional imidate (2eq) was added in portions over a period of 6 hours. The reaction mixturewas cooled to ambient temperature. A solid was isolated by filtrationand rinsed with dichloromethane. The solid was stirred with water for 30minutes, isolated by filtration, and then dried to provide 2.77 g of1-(2-chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexanol.

Part B

A portion (2.34 g, 7.09 mmol) of the material from Part A was oxidizedand then animated using the method of Part I of Example 12 except thatthe amination was run at ambient temperature. The crude product wastriturated with acetonitrile to provide 0.57 g of1-{[4-amino-2-(chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexanolas a tan solid.

Part C

Potassium acetate (0.28 g, 2.89 mmol) was added to a solution of1-{[4-amino-2-(chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexanol(0.83 g, 2.41 mmol) in DMF (10 mL). The reaction mixture was stirred atambient temperature overnight and then concentrated under reducedpressure to provide crude[4-amino-1-(1-hydroxycyclohexylmethyl)-1H-imidazo[4,5-c]quinolin-2-yl]methylacetate.

Part D

Potassium carbonate (0.67 g, 4.82 mmol) was added to a solution of thematerial from Part C in methanol (10 mL). The reaction mixture wasstirred at ambient temperature for 1 hour and then concentrated underreduced pressure. The residue was triturated sequentially with water andhot acetonitrile and then dried in a vacuum oven at 85° C. to provide0.458 g of1-{[4-amino-2-(hydroxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexanolas tan needles, mp 244-248° C. MS (ESI) m/z 327 (M+H)⁺; Anal. calcd forC₁₈H₂₂N₄O₂: C, 66.24; H, 6.79; N, 17.17. Found: C, 66.23; H, 6.57; N,17.04.

Example 814-[2-(4-Amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]tetrahydro-2H-pyran-4-ol

Part A

N-{2-[4-tert-butyldimethylsilanyloxy)tetrahydropyran-4-yl]ethyl}-3-nitroquinolin-4-aminewas prepared according to the general method of Part A of Example 74except that tetrahydropyran-4-one was used in lieu of cyclohexanone.

Part B

Acetic acid (27 mL) and water (9 mL) were added to a solution ofN-{2-[4-tert-butyldimethylsilanyloxy)tetrahydropyran-4-yl]ethyl}-3-nitroquinolin-4-aminein tetrahydrofuran (THF, 9 mL). The reaction mixture was heated at 50°C. for 2 hours. Analysis indicated that the protecting group was stillin place. 6M hydrochloric acid (5 mL) was added, the reaction mixturewas heated at 50° C. for 48 hours, and then concentrated under reducedpressure. The residue was slurried with aqueous saturated sodiumbicarbonate (50 mL) and the pH was adjusted to 8 with solid sodiumbicarbonate. A solid was isolated by filtration and then triturated withdichloromethane to provide 3.43 g of4-[2-(3-nitroquinolin-4-ylamino)ethyl]tetrahydropyran-4-ol as a yellowsolid.

Part C

A mixture of the material from Part B (3.43 g, 10.8 mmol), 5% platinumon carbon (0.34 g), and ethyl acetate (50 mL) was placed under hydrogenpressure (40 psi, 2.8×10⁵ Pa) for 3 hours. The reaction mixture wasfiltered through a layer of CELITE filter aid and the filter cake wasrinsed with ethyl acetate (100 mL). The filtrate was concentrated underreduced pressure to provide 2.92 g of4-[2-(3-aminoquinolin-4-ylamino)ethyl]tetrahydropyran-4-ol as a yellowsolid.

Part D

Trimethylorthobutyrate (0.93 mL, 5.88 mmol) and pyridine hydrochloride(27 mg, 0.23 mmol) were added to a suspension of a portion (1.30 g, 4.52mmol) of the material from Part C in toluene (20 mL). The reactionmixture was heated at reflux for 3 hours, allowed to cool to ambienttemperature, and then concentrated under reduced pressure. The residuewas dissolved in dichloromethane (20 mL), decolorized with charcoal, andthen concentrated under reduced pressure to provide a yellow solid. Thismaterial was recrystallized from acetonitrile to provide 0.491 g of4-[2-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]tetrahydro-2H-pyran-4-olas white needles, mp 186-188° C. MS (ESI) m/z 340 (M+H)⁺; Anal. calcdfor C₂₀H₂₅N₃O₂: C, 70.77; H, 7.42; N, 12.38. Found: C, 70.63; H, 7.31;N, 12.43.

Part E

The material from Part D was oxidized and then animated using the methodof Part I of Example 12. The crude product was triturated with 2M sodiumhydroxide. The resulting solid was recrystallized fromchloroform/hexanes and dried under vacuum at 85° C. to provide 0.322 gof4-[2-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]tetrahydro-2H-pyran-4-olas beige needles, mp 181-183° C. MS (ESI) m/z 355 (M+H)⁺; Anal. calcdfor C₂₀H₂₆N₄O₂: C, 67.77; H, 7.39; N, 15.81. Found: C, 67.62; H, 7.59;N, 15.84.

Example 824-[2-(4-Amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]tetrahydro-2H-pyran-4-ol

Part A

4-[2-(2-Methyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]tetrahydro-2H-pyran-4-olwas prepared according to the methods of Parts A through D of Example 81except that trimethylorthoacetate was used in lieu oftrimethylorthobutyrate in Part D. The crude product was triturated withacetonitrile to provide 0.69 g of product as a grey solid.

Part B

The material from Part A was oxidized and then animated using the methodof Part I of Example 12. The crude product was triturated with 2M sodiumhydroxide. The resulting solid was recrystallized fromchloroform/hexanes and dried under vacuum at 120° C. to provide 0.363 gof4-[2-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]tetrahydro-2H-pyran-4-olas beige needles, mp greater than 253° C. MS (ESI) m/z 327 (M+H)⁺; Anal.calcd for C₁₈H₂₂N₄O₂: C, 66.24; H, 6.79; N, 17.17. Found: C, 65.98; H,6.80; N, 16.97.

Example 834-[2-(4-Amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]tetrahydro-2H-pyran-4-ol

Part A

4-[2-(2-Ethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]tetrahydro-2H-pyran-4-olwas prepared according to the methods of Parts A through D of Example 81except that triethylorthopropionate was used in lieu oftrimethylorthobutyrate in Part D. The crude product was triturated withacetonitrile to provide 0.78 g of product as a grey solid.

Part B

The material from Part A was oxidized and then animated using the methodof Part I of Example 12. The crude product was triturated with 2M sodiumhydroxide. The resulting solid was recrystallized fromchloroform/hexanes and dried under vacuum at 120° C. to provide 0.405 gof4-[2-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]tetrahydro-2H-pyran-4-olas yellow needles, mp 243-244° C. MS (ESI) m/z 341 (M+H)⁺; Anal. calcdfor C₁₉H₂₄N₄O₂: C, 67.04; H, 7.11; N, 16.46. Found: C, 66.81; H, 7.28;N, 16.29.

Example 841-[2-(4-Amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]cyclopropanol

Part A

Sodium carbonate (21.1 g, 199 mmol) was added to a suspension ofβ-alanine ethyl ester hydrochloride (10.2 g, 66.4 mmol) and benzylbromide (16.2 mL, 136 mmol) in acetonitrile (265 mL). The reactionmixture was stirred at ambient temperature overnight and then filteredthrough a layer of CELITE filter aid. The filter cake was rinsed withacetonitrile (100 mL). The filtrate was concentrated under reducedpressure to provide 20.28 g of ethyl 3-dibenzylaminopropionate as a paleyellow oil.

Part B

Titanium(IV) isopropoxide (3.9 mL, 13.28 mmol) was added to a solutionof the material from Part A in diethyl ether. The mixture was cooled to4° C. and ethylmagnesium bromide (63 mL of 3.16 M in diethyl ether) wasadded dropwise over a period of 90 minutes while maintaining thetemperature at 1.5-4° C. The reaction mixture was stirred at ambienttemperature overnight. Hydrochloric acid (75 mL of 3 M) was added andthe reaction mixture was stirred at ambient temperature for 2 hours. Thereaction mixture was made basic with solid sodium bicarbonate anddiluted with water (200 mL). The layers were separated. The aqueouslayer was extracted with diethyl ether (4×100 mL). The combined organicswere dried over magnesium sulfate, filtered, and then concentrated underreduced pressure to provide a yellow oil. This material was purified byHPFC eluting with a gradient of 0 to 40% ethyl acetate in hexanes toprovide 6.73 g of 1-[2-(dibenzylamino)ethyl]cyclopropanol as a paleyellow oil.

Part C

Ammonium formate (6.03 g, 95.7 mmol) and 10% palladium on carbon (1.10g) were added to a solution of the material from Part B in methanol (95mL). The reaction mixture was stirred at 65° C. for 2 hours and thenfiltered through a layer of CELITE filter aid. The filter cake wasrinsed with methanol (70 mL). The filtrate was concentrated underreduced pressure to provide 2.78 g of crude1-(2-aminoethyl)cyclopropanol.

Part D

The material from Part C was dissolved in a mixture of dichloromethane(65 mL) and triethylamine (6.0 mL, 43.4 mmol). The solution was cooledto 0° C. and then 4-chloro-3-nitroquinoline (4.53 g, 21.7 mmol) wasadded in portions over a period of 5 minutes. The reaction mixture wasstirred over the weekend while slowly warming to ambient temperature.The reaction mixture was diluted with dichloromethane (20 mL) andaqueous saturated sodium bicarbonate (40 mL). The layers were separatedand the aqueous layer was extracted with dichloromethane (2×15 mL). Thecombined organics were dried over magnesium sulfate, filtered, and thenconcentrated under reduced pressure. The residue was triturated withacetonitrile to provide 3.16 g of1-[2-(3-nitroquinolin-4-ylamino)ethyl]cyclopropanol as a yellow solid.

Part E

A mixture of the material from Part D, 5% platinum on carbon (0.32 g),and ethyl acetate (50 mL) was placed under hydrogen pressure (40 psi,2.8×10⁵ Pa) for 3 hours. The reaction mixture was filtered through alayer of CELITE filter aid and the filter cake was rinsed with ethylacetate (75 mL). The filtrate was concentrated under reduced pressure toprovide crude 1-[2-(3-aminoquinolin-4-ylamino)ethyl]cyclopropanol.

Part F

Triethylorthopropionate (1.2 mL, 5.78 mmol) and pyridine hydrochloride(45 mg, 0.39 mmol) were added to a suspension of the material from PartE in toluene (16 mL). The reaction mixture was heated at reflux for 2.5hours, allowed to cool to ambient temperature, and the precipitate wasisolated by filtration to provide 0.68 g of1-[2-(2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]cyclopropanol as awhite solid.

Part G

The material from Part F was oxidized and then aminated according to thegeneral method of Part I of Example 12. The crude product was trituratedwith 2M sodium hydroxide, recrystallized from chloroform/methanol 99/1and hexanes, and then dried in a vacuum oven at 85° C. to provide 300 mgof1-[2-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]cyclopropanolas white needles, mp 199-200° C. MS (ESI) m/z 297 (M+H)⁺; Anal. calcdfor C₁₇H₂₀N₄O: C, 68.90; H, 6.80; N, 18.90. Found: C, 68.72; H, 7.04; N,18.83.

Example 851-[2-(4-Amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]cyclopropanol

1-[2-(4-Amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]cyclopropanolwas prepared and purified according to the methods of Parts A through Gof Example 84 using trimethylorthoacetate in lieu oftriethylorthopropionate in Part F. The product was provided as whiteneedles, mp decomposed at 203° C. MS (ESI) m/z 283 (M+H)⁺; Anal. calcdfor C₁₆H₁₈N₄O: C, 68.06; H, 6.43; N, 19.84. Found: C, 67.86; H, 6.33; N,19.87.

Example 861-[2-(4-Amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]cyclopropanol

Part A

Ethoxyacetyl chloride (0.43 mL) was added to a cooled (0° C.) solutionof 1-[2-(3-aminoquinolin-4-ylamino)ethyl]cyclopropanol (3.85 mmol) indichloromethane (16 mL). The reaction mixture was stirred at 0-5° C. for60 minutes and then concentrated under reduced pressure to provide crude2-ethoxy-N-{4-[2-(1-hydroxycyclopropyl)ethylamino]quinolin-3-yl}acetamidehydrochloride.

Part B

Triethylamine (1.6 mL) was added to a solution of the material from PartA in ethanol (16 mL). The reaction mixture was stirred at ambienttemperature overnight and then at 60° C. for 2 hours. The reactionmixture was concentrated under reduced pressure and the residue waspartitioned between dichloromethane (50 mL) and aqueous saturated sodiumbicarbonate (40 mL). The aqueous layer was separated and extracted withdichloromethane (2×20 mL). The combined organics were dried overmagnesium sulfate, filtered, and then concentrated under reducedpressure to provide a green solid. This material was triturated withacetonitrile to provide 0.77 g of1-[2-(2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]cyclopropanolas a white solid.

Part C

The material from Part F was oxidized and then aminated according to thegeneral method of Part I of Example 12. The crude product was trituratedwith 2M sodium hydroxide, recrystallized from chloroform/methanol 99/1and hexanes, and then dried in a vacuum oven at 85° C. to provide 0.333g of1-[2-(4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]cyclopropanolas white needles, mp 210-211° C. MS (ESI) m/z 327 (M+H)⁺; Anal. calcdfor C₁₈H₂₂N₄O₂: C, 66.24; H, 6.79; N, 17.17. Found: C, 65.98; H, 6.82;N, 17.08.

Example 871-[3-(4-Amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]cyclopropanol

1-[3-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]cyclopropanolwas prepared according to the general methods of Parts A through G ofExample 84 except that ethyl 4-aminobutyrate hydrochloride was used inlieu of β-alanine ethyl ester hydrochloride in Part A andtrimethylorthoacetate was used in lieu of triethylorthopropionate inPart F. The crude product was triturated with 2M sodium hydroxide andthe resulting tan solid was purified by HPFC eluting with a gradient of0 to 60% CMA in chloroform to provide 0.57 g of an off white solid. Thismaterial was triturated with hot acetonitrile and then dried in a vacuumoven at 85° C. to provide 0.34 g of product as off-white needles, mp210-212° C. MS (ESI) m/z 297 (M+H)⁺; Anal. calcd for C₁₇H₂₀N₄O: C,68.90; H, 6.80; N, 18.90. Found: C, 68.69; H, 7.06; N, 19.07.

Example 881-[(4-Amino-2-ethyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]cyclopropanol

Part A

Ethyl bromoacetate (19.52 mL, 176 mol) was added in a single portion toa chilled (0° C.) solution of dibenzylamine (33.84 mL, 176 mmol) andtriethylamine (27 mL, 193.6 mmol) in THF. The reaction mixture wasstirred overnight at ambient temperature. Additional triethylamine (30mL) and THF (100 mL) were added and the reaction mixture was heated at50° C. for 1.5 hours. Additional ethyl bromoacetate (13 mL) was addedand the reaction mixture was heated for 1 hour and then stirred atambient temperature overnight. About half of the THF was removed underreduced pressure. The mixture was diluted with water (300 mL) and thenextracted with ethyl acetate (2×400 mL). The combined extracts werewashed sequentially with water and with brine, dried over sodiumsulfate, filtered, and then concentrated under reduced pressure. Theresidue was purified by flash chromatography (700 g of silica gel,eluting with 20% ethyl acetate in hexanes) to provide 37.12 g of ethyldibenzylaminoacetate as a colorless oil.

Part B

1-[(4-Amino-2-ethyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]cyclopropanolwas prepared according to the general methods of Parts B through G ofExample 84 using ethyl dibenzylaminoacetate in lieu of ethyl3-dibenzylaminopropionate in Part B and 4-chloro-3-nitronaphthyridine inlieu of 4-chloro-3-nitroquinoline in Part D. The crude product wastriturated with acetonitrile to provide a tan solid. This material waspurified by HPFC eluting with a gradient of 0-35% CMA in chloroform toprovide an off white solid. This material was triturated with hotacetonitrile and then dried in a vacuum oven at 85° C. to provide 0.515g of product as an off-white solid, mp 210-212° C. MS (APCI) m/z 284(M+H)⁺; Anal. calcd for C₁₅H₁₇N₅O: C, 63.59; H, 6.05; N, 24.72. Found:C, 63.27; H, 5.99; N, 25.06.

Example 891-{[4-Amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclopropanol

Part A

1-[(3-Aminoquinolin-4-ylamino)methyl]cyclopropanol was preparedaccording to the methods of Parts B through E of Example 84 using ethyldibenzylaminoacetate in lieu of ethyl 3-dibenzylaminopropionate in PartB.

Part B

1-{[4-Amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclopropanolwas prepared according to the methods of Parts A through C of Example 86using 1-[(3-aminoquinolin-4-ylamino)methyl]cyclopropanol in lieu of1-[2-(3-aminoquinolin-4-ylamino)ethyl]cyclopropanol in Part A. The crudewas purified by HPFC eluting with a gradient of 0-50% CMA in chloroformto provide a tan solid. This material was recrystallized from chloroformand hexanes and dried in a vacuum oven at 85° C. to provide product astan crystals, mp 185-186° C. MS (ESI) m/z 313 (M+H)⁺; Anal. calcd forC₁₇H₂₀N₄O₂: C, 65.37; H, 6.45; N, 17.94. Found: C, 65.14; H, 6.43; N,17.92.

Example 901-[(4-Amino-2-propyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]cyclopropanol

1-[(4-Amino-2-propyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]cyclopropanolwas prepared according to the general methods of Parts D through G ofExample 84 using 1-(aminomethyl)cyclopropanol in lieu of1-(2-aminoethyl)cyclopropanol in Part D, 4-chloro-3-nitronaphthyridinein lieu of 4-chloro-3-nitroquinoline in Part D, and trimethylorthobutyrate in lieu of triethyl orthopropionate in Part F. The crudeproduct was triturated with hot acetonitrile to provide a tan solid.Which was recrystallized from chloroform and hexanes and dried at 140°C. under vacuum to provide product as an off-white solid, mp 199-200° C.MS (ESI) m/z 298 (M+H)⁺; Anal. calcd for C₁₆H₁₉N₅O: C, 64.63; H, 6.44;N, 23.55. Found: C, 64.32; H, 6.62; N, 23.67.

Example 911-[(4-Amino-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]cyclopropanol

1-[(4-Amino-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]cyclopropanolwas prepared according to the general methods of Example 89 using4-chloro-3-nitronaphthyridine in lieu of 4-chloro-3-nitroquinoline inPart A. The crude product was purified by HPFC eluting with a gradientof 0-35% CMA in chloroform followed by recrystallization from hotacetonitrile to provide product as an off-white solid, mp 178-179° C. MS(APCI) m/z 314 (M+H)⁺; Anal. calcd for C₁₆H₁₉N₅O₂: C, 61.33; H, 6.11; N,22.35. Found: C, 60.99; H, 6.09; N, 22.52.

Example 92N-(1-{[4-Amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclopropyl)methanesulfonamide

Part A

Ethyl cyanoacetate (15 mL, 141 mmol) was added to a mixture of potassiumcarbonate (48.7 g, 353 mmol) and acetone (200 mL). 1,2-Dibromoethane(13.4 mL, 155 mmol) was added dropwise over a period of 8 minutes. Thereaction mixture was refluxed overnight. More 1,2-dibromoethane (1.8 mL)was added and the reaction mixture was refluxed for 4 hours. Thereaction mixture was filtered through a layer of CELITE filter aid. Thefilter cake was rinsed with acetone (200 mL). The filtrate wasconcentrated under reduced pressure to provide ethyl1-cyanocyclopropionate as a pale orange oil.

Part B

Concentrated hydrochloric acid (25 mL) and platinum oxide (0.98 g) wereadded to a solution of the material from Part A in ethanol (225 mL). Themixture was placed under hydrogen pressure (40 psi, 2.8×10⁵ Pa) on aParr apparatus for 20 hours. The reaction mixture was filtered through alayer of CELITE filter aid. The filter cake was rinsed with methanol(200 mL). The filtrate was concentrated under reduced pressure. Theresidue was reconcentrated under reduced pressure three times frommethanol and twice from toluene to provide 31.7 g of ethyl1-aminomethylcyclopropionate hydrochloride.

Part C

Triethylamine (41 mL, 294 mmol) was added to a suspension of4-chloro-3-nitroquinoline (24.5 g, 118 mmol) in dichloromethane (250mL). The mixture was cooled to 5° C. A solution of the material fromPart B in dichloromethane (200 mL) was added over a period of 15minutes. The reaction mixture was stirred at 5° C. for 1 hour and thenat ambient temperature overnight. The reaction mixture was washed withaqueous saturated sodium bicarbonate (250 mL). The aqueous layer wasback extracted with dichloromethane (2×50 mL). The combined organicswere dried over magnesium sulfate, filtered, and then concentrated underreduced pressure to provide an orange oil. This material wasrecrystallized from acetonitrile to provide 21.47 g of ethyl1-[(3-nitroquinolin-4-ylamino)methyl]cyclopropionate as a bright yellowsolid.

Part D

A mixture of material from Part C (8.0 g, 25.4 mmol), 5% platinum oncarbon (0.80 g), and ethyl acetate (100 mL) was placed under hydrogenpressure (30 psi, 2.1×10⁵ Pa) on a Parr apparatus for 3 hours. Thereaction mixture was filtered through a layer of CELITE filter aid. Thefilter cake was rinsed with ethyl acetate (50 mL). The filtrate wasconcentrated under reduced pressure to provide ethyl1-[(3-aminoquinolin-4-ylamino)methyl]cyclopropionate as a yellow solid.

Part E

Ethoxyacetyl chloride (2.9 mL, 28 mmol) was added dropwise over a periodof 5 minutes to a chilled (0° C.) solution of the material from Part Din dichloromethane (100 mL). The reaction mixture was allowed to slowlywarm to ambient temperature overnight and then concentrated underreduced pressure to provide crude ethyl1-{[3-(2-ethoxyacetylamino)quinolin-4-ylamino]methyl]cyclopropionatehydrochloride.

Part F

Triethylamine (10.6 mL, 76.2 mmol) was added to a solution of thematerial from Part E in ethanol (100 mL). The reaction mixture washeated at 60° C. overnight and then concentrated under reduced pressure.The residue was dissolved in dichloromethane (100 mL) and washed withaqueous saturated sodium bicarbonate (75 mL). The aqueous layer was backextracted with dichloromethane (2×35 mL). The combined organics weredried over magnesium sulfate, filtered, and then concentrated underreduced pressure to provide 9.5 g of ethyl1-[(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]cyclopropionateas a brown semisolid.

Part G

Sodium hydroxide (8.5 mL of 6 M) was added to a solution of the materialfrom Part F in ethanol (80 mL). The reaction mixture was stirred atambient temperature for 3 hours and then concentrated under reducedpressure. The residue was slurried with water (60 mL). The pH of themixture was adjusted to 12 and then it was extracted with diethyl ether(3×20 mL). The pH of the aqueous was adjusted to 4 and a precipitateformed. The precipitate was isolated by filtration to provide 4.36 g of1-[(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]cyclopropropanecarboxylicacid.

Part H

Triethylamine (3.9 mL, 27.7 mol) and diphenylphosphoryl azide (2.2 mL,10.1 mmol) were added to a chilled (0° C.) suspension of material fromPart G (3.00 g, 9.2 mmol) in toluene (45 mL). The reaction mixture wasstirred at 0° C. for 2 hours, warmed to ambient temperature, and thenstirred for an additional 4 hours. Tert-butanol was added and thereaction mixture was refluxed overnight. The reaction mixture wasdiluted with dichloromethane (50 mL) and aqueous saturated sodiumbicarbonate (75 mL). The aqueous was back extracted with dichloromethane(2×30 mL). The combined organics were dried over magnesium sulfate,filtered, and then concentrated under reduced pressure to provide 3.41 gof tert-butyl{1-[(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]cyclopropyl}carbamateas an off white foam.

Part I

Hydrochloric acid (2 mL of 6M) was added to a solution of material fromPart H (0.49 g, 1.24 mmol) in ethanol (4 mL). The reaction mixture washeated at 50° C. for 4 hours, cooled to ambient temperature, and thenconcentrated under reduced pressure. The residue was concentrated underreduced pressure from methanol 3 times. The resulting solid wastriturated with acetonitrile to provide 0.43 g of1-[(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]cyclopropylaminehydrochloride.

Part J

Methanesulfonyl chloride (0.12 mL, 1.6 mmol) was added dropwise to achilled (0° C. solution of the material from Part I in dichloromethane(8 mL) and triethylamine (0.52 mL, 3.7 mmol). The reaction mixture wasallowed to stir at 0-5° C. for 2.5 hours. The reaction mixture wasdiluted with dichloromethane (25 mL) and aqueous saturated sodiumbicarbonate (25 mL). The aqueous was back extracted with dichloromethane(2×10 mL). The combined organics were dried over magnesium sulfate,filtered, and then concentrated under reduced pressure to provide 0.48 gofN-(1-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclopropyl)methanesulfonamideas a white solid.

Part K

The material from Part J was oxidized and then aminated according to themethods of Part I of Example 12. The crude product was purified by HPFCeluting with a gradient of 0-35% CMA in chloroform to provide a yellowgooey solid. This material was combined with 2M hydrochloric acid andstirred for 1 hour. The mixture was made basic (pH 8) with solid sodiumbicarbonate. The resulting solid was isolated by filtration, washed withwater, and then dried in a vacuum oven at 85° C. to provide 201 mg ofN-(1-{[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclopropyl)methanesulfonamideas white needles, mp dehydrates at 98 C, no discernible melting point °C. MS (ESI) m/z 390 (M+H)⁺; Anal. calcd for C₁₈H₂₃N₅O₃S*1.8 H₂O: C,51.24; H, 6.35; N, 16.60. Found: C, 51.19; H, 6.36; N, 16.38.

Example 931-[(4-Amino-2-ethoxymethyl-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl]cyclohexanol

Part A

1-[(3-Amino-2-dibenzylamino-5,6-dimethylpyridin-4-ylamino)methyl]cyclohexanol(0.94 g, 2.1 mmol, prepared as described in Parts A through C of Example59 was reacted with ethoxyacetyl chloride (0.31 g, 2.52 mmol) accordingto the general method of Part A of Example 58. The resulting amide wascyclized according to the general method of Part A of Example 58 toprovide 0.67 g of1-[(4-dibenzylamino-2-ethoxymethyl-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl]cyclohexanolas a white solid.

Part B

The benzyl groups were removed from the material from Part A using thegeneral method of Part E of Example 59. The crude product wasrecrystallized from acetonitrile to provide 321 mg of1-[(4-amino-2-ethoxymethyl-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl]cyclohexanolas white needles, mp 194.0-195.0° C. Anal. Calcd for C₁₈H₂₈N₄O₂ C,65.03; H, 8.49; N, 16.85. Found: C, 64.92; H, 8.42; N, 17.11.

Example 942-Ethoxymethyl-1-(1-methoxycyclohexyl)-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine

Part A

Under a nitrogen atmosphere iodomethane (0.58 mL, 9.3 mmol) and1-[(4-dibenzylamino-2-ethoxymethyl-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl]cyclohexanol(1.59 g, 3.10 mmol) were added to a mixture of potassium hydride (0.87 gof 30 wt %, 6.5 mmol) and tetrahydrofuran (31 mL). The reaction mixturewas stirred at ambient temperature for 1 hour and then quenched withmethanol. Water and a few drops of acetic acid were added until thereaction mixture was slightly acidic. The volume of the reaction mixturewas reduced under vacuum and then it was diluted with water (20 mL) andhexanes (20 mL). A solid was isolated by filtration, rinsed with waterand hexanes, and then dried in a vacuum oven at 70° C. to provide 1.50 gofdibenzyl[2-ethoxymethyl-1-(1-methoxycyclohexyl)-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-yl]amine.

Part B

The benzyl groups were removed from the material from Part A using thegeneral method of Part E of Example 59. The crude product wasrecrystallized from acetonitrile. The resulting solid was dissolved indichloromethane (150 mL), washed with saturated aqueous sodiumbicarbonate (50 mL) and brine (30 mL), dried over sodium sulfate,filtered, and concentrated under reduced pressure. The residue wasrecrystallized from acetonitrile to provide2-ethoxymethyl-1-(1-methoxycyclohexyl)-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-amineas white needles, mp 172.0-173.0° C. Anal. Calcd for C₁₉H₃₀N₄O₂ C,65.87; H, 8.73; N, 16.17. Found: C, 65.64; H, 8.93; N, 16.32.

Example 951-(1-Methoxycyclohexyl)-6,7-dimethyl-2-propyl-1H-imidazo[4,5-c]]pyridin-4-amine

1-(1-Methoxycyclohexyl)-6,7-dimethyl-2-propyl-1H-imidazo[4,5-c]pyridin-4-aminewas prepared according to the general methods of Example 94 using1-[(4-dibenzylamino-6,7-dimethyl-2-propyl-1H-imidazo[4,5-]pyridin-1-yl)methyl]cyclohexanol(Example 59, Parts A through D) in lieu of1-[(4-dibenzylamino-2-ethoxymethyl-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl]cyclohexanolin Part A. The crude product was recrystallized from acetonitrile toprovide pure product as white needles, mp 192.0-193.0° C. Anal. Calcdfor C₁₉H₃₀N₄O C, 69.06; H, 9.15; N, 16.95. Found: C, 68.79; H, 9.27; N,16.88.

Example 962-Ethoxymethyl-1-(1-methoxycyclohexyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine

Part A

1-[(2-Ethoxymethyl-1H-imidazo[4,5-c][1,5]napthyridin-1-yl)methyl]cyclohexanol(1.87 g, 5.49 mmol, Example 58 Part A) was treated with iodomethaneaccording to the general method of Part A of Example 94 to provide 1.75g of2-ethoxymethyl-1-(1-methoxycyclohexyl)-1H-imidazo[4,5-c][1,5]naphthyridine.

Part B

The material from Part A was oxidized and then aminated according to thegeneral method of Part D of Example 57. The crude product was purifiedtwice by HPFC eluting the first time with a gradient of 0-35% CMA inchloroform and the second time with a gradient of 0-30% CMA inchloroform and then recrystallized from acetonitrile to provide 304 mgof2-ethoxymethyl-1-(1-methoxycyclohexyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amineas an off-white powder, mp 160.0-161.0° C. Anal. Calcd for C₂₀H₂₇N₅O₂ C,65.02; H, 7.37; N, 18.96. Found: C, 65.03; H, 7.43; N, 18.94.

Example 971-(1-Methoxycyclohexyl)-2-propyl-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine

1-(1-Methoxycyclohexyl)-2-propyl-1H-imidazo[4,5-c][1,5]naphthyridin-4-aminewas prepared according to the general methods of Example 96 using1-[(2-propyl-1H-imidazo[4,5-c][1,5]napthyridin-1-yl)methyl]cyclohexanolin lieu of1-[(2-ethoxymethyl-1H-imidazo[4,5-c][1,5]napthyridin-1-yl)methyl]cyclohexanol.The crude product was purified twice by HPFC eluting with a gradient of0-30% CMA in chloroform and then triturated twice with acetonitrile toprovide pure product as an off-white powder, mp 187.0-188.0° C. Anal.Calcd for C₂₀H₂₇N₅O C, 67.96; H, 7.70; N, 19.81. Found: C, 67.63; H,7.84; N, 19.96.

Example 981-[(4-Amino-2-propyl-1H-imidazo[4,5-c][1,5]napthyridin-1-yl)methyl]cyclopentanol

1-[(4-Amino-2-propyl-1H-imidazo[4,5-c][1,5]napthyridin-1-yl)methyl]cyclopentanolwas prepared according to the general methods of Example 57 Parts Athrough D using 1-(aminomethyl)cyclopentanol in lieu of1-(aminomethyl)cyclohexanol in Part A. The crude product was purified byHPFC eluting with a gradient of 0-30% CMA in chloroform and thentriturated sequentially with acetonitrile and ethyl acetate to providepure product as a white powder, mp 184.0-186.0° C. Anal. Calcd forC₁₈H₂₃N₅O C, 66.44; H, 7.12; N, 21.52. Found: C, 66.18; H, 7.31; N,21.45.

Example 991-[(4-Amino-2-propyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-c][1,5]napthyridin-1-yl)methyl]cyclopentanol

A mixture of1-[(4-amino-2-propyl-1H-imidazo[4,5-c][1,5]napthyridin-1-yl)methyl]cyclopentanol(511 mg), platinum oxide (511 mg), and trifluoroacetic acid was placedunder hydrogen pressure (50 psi, 3.4×10⁵ Pa) overnight on a Parrapparatus. The mixture was filtered through a layer of CELITE filter aidand the filter cake was rinsed with methanol. The filtrate wasconcentrated under reduced pressure. The residue was combined withconcentrated hydrochloric acid (2 mL) and stirred at ambient temperaturefor 2 hours. The mixture was diluted with water (10 mL) and then cooledto 0° C. The pH was adjusted to 12 with 6N sodium hydroxide and then themixture was extracted with dichloromethane (3×50 mL). The combinedorganics were washed with brine (20 mL), dried over sodium sulfate,filtered, and then concentrated under reduced pressure. The residue wastriturated with acetonitrile, purified by HPFC eluting with a gradientof 0-35% CMA in chloroform, and then triturated with acetonitrile toprovide 167 mg of1-[(4-amino-2-propyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-c][1,5]napthyridin-1-yl)methyl]cyclopentanolas a white powder, mp 207.0-208.0° C. Anal. Calcd for C₁₈H₂₇N₅O.0.25H₂OC, 64.74; H, 8.30; N, 20.97. Found: C, 64.71; H, 8.29; N, 20.98.

Example 1001-[(4-Amino-2-ethoxymethyl-1H-imidazo[4,5-c][1,5]napthyridin-1-yl)methyl]cyclopentanol

1-[(4-Amino-2-ethoxymethyl-1H-imidazo[4,5-c][1,5]napthyridin-1-yl)methyl]cyclopentanolwas prepared according to the general methods of Example 58 using1-(aminomethyl)cyclopentanol in lieu of 1-(aminomethyl)cyclohexanol. Thecrude product was purified by HPFC eluting with a gradient of 0-30% CMAin chloroform, triturated with acetonitrile, and then recrystallizedfrom ethyl acetate/hexanes to provide pure product as an off-whitepowder, mp 165.0-166.0° C. Anal. Calcd for C₁₈H₂₃N₅O₂ C, 63.32; H, 6.79;N, 20.51. Found: C, 63.07; H, 7.01; N, 20.35.

Example 1011-[(4-Amino-2-ethoxymethyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-c][1,5]napthyridin-1-yl)methyl]cyclopentanol

1-[(4-Amino-2-ethoxymethyl-1H-imidazo[4,5-c][1,5]napthyridin-1-yl)methyl]cyclopentanol(503 mg) was reduced according to the method of Example 100. The crudeproduct was triturated twice with acetonitrile to provide 329 mg of pureproduct as a white powder, mp 207.0-208.0° C. Anal. Calcd for C₁₈H₂₇N₅O₂C, 62.59; H, 7.88; N, 20.27. Found: C, 62.36; H, 7.82; N, 20.42.

Example 1021-[(4-Amino-2-propyl-1H-imidazo[4,5-c][1,5]napthyridin-1-yl)methyl]cyclobutanol

1-[(4-Amino-2-propyl-1H-imidazo[4,5-c][1,5]napthyridin-1-yl)methyl]cyclobutanolwas prepared according to the general methods of Example 57 Parts Athrough D using 1-(aminomethyl)cyclobutanol in lieu of1-(aminomethyl)cyclohexanol in Part A. The crude product was trituratedsequentially with acetonitrile and ethyl acetate and then recrystallizedfrom chloroform/hexanes to provide pure product as a white powder, mp226.0-227.0° C. Anal. Calcd for C₁₇H₂₁N₅O.0.1H₂O C, 65.20; H, 6.82; N,22.36. Found: C, 64.95; H, 6.94; N, 22.40.

Example 1031-[(4-Amino-2-ethoxymethyl-1H-imidazo[4,5-c][1,5]napthyridin-1-yl)methyl]cyclobutanol

1-[(4-Amino-2-ethoxymethyl-1H-imidazo[4,5-c][1,5]napthyridin-1-yl)methyl]cyclobutanolwas prepared according to the general methods of Example 58 using1-(aminomethyl)cyclobutanol in lieu of 1-(aminomethyl)cyclohexanol. Thecrude product was triturated sequentially with acetonitrile and ethylacetate, recrystallized twice from chloroform/hexanes, purified by HPFCeluting with a gradient of 0-25% CMA in chloroform, and then trituratedwith acetonitrile to provide pure product as a white powder, mp162.0-163.0° C. Anal. Calcd for C₁₇H₂₁N₅O₂.0.2H₂O C, 61.69; H, 6.52; N,21.16. Found: C, 61.51; H, 6.47; N, 21.13.

Example 1041-[(4-Amino-2-hydroxymethyl-1H-imidazo[4,5-c][1,5]napthyridin-1-yl)methyl]cyclobutanol

Under a nitrogen atmosphere boron tribromide (6.15 mL of 1M indichloromethane) was added dropwise over a period of 10 minutes to achilled (0° C.) solution of1-[(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c][1,5]napthyridin-1-yl)methyl]cyclobutanol(0.67 g, 2.0 mmol) in dichloromethane (20 mL). The reaction mixture wasallowed to warm to ambient temperature and was stirred overnight. Thereaction mixture was cooled to 0° C. and then more boron tribromide (1.0mL) was added. The reaction mixture was stirred at ambient temperaturefor 4 hours. Methanol (10 mL) and hydrochloric acid (10 mL of 6N) wereadded and the reaction mixture was heated at reflux for 1 hour. Thereaction mixture was allowed to cool to ambient temperature and was thenmade basic with 6N sodium hydroxide. A portion of the solvent wasremoved under vacuum, water (10 mL) was added, and the mixture wassonicated. A solid was isolated by filtration and rinsed with water. Theaqueous filtrate was extracted with chloroform (3×80 mL). The combinedorganics were washed with brine (20 mL), dried over sodium sulfate,filtered, and then concentrated under reduced pressure. The residue wascombined with the isolated solid and then purified by HPFC eluting witha gradient of 0-30% CMA in chloroform, triturated with acetonitrile, anddried. The resulting material was suspended in water (70 mL) and heatedto 90° C. Concentrated hydrochloric acid (about 0.8 mL) was added untila solution was obtained. The hot solution was made basic with solidsodium bicarbonate and then allowed to cool. A precipitate was isolatedby filtration, washed well with water, and then dried to provide1-[(4-amino-2-hydroxymethyl-1H-imidazo[4,5-c][1,5]napthyridin-1-yl)methyl]cyclobutanolas a white powder, mp 244.0-246.0° C. Anal. Calcd for C₁₅H₁₇N₅O₂ C,60.19; H, 5.72; N, 23.40. Found: C, 59.97; H, 5.81; N, 23.31.

Example 1051-[(4-Amino-2-propyl-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl]cyclobutanol

1-[(4-Amino-2-propyl-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl]cyclobutanolwas prepared according to the general methods of Example 59 using1-(aminomethyl)cyclobutanol in lieu of 1-(aminomethyl)cyclohexanol inPart A. The crude product was triturated with acetonitrile, purified byHPFC eluting with a gradient of 0-50% CMA in chloroform, triturated with1N sodium hydroxide, washed with water, dried, triturated with hot ethylacetate, and then dried to provide pure product as a white powder, mp180.0-181.0° C. Anal. Calcd for C₁₆H₂₄N₄O C, 66.64; H, 8.39; N, 19.43.Found: C, 66.49; H, 8.74; N, 19.60.

Example 1061-[(4-Amino-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl]cyclobutanol

1-[(4-amino-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl]cyclobutanolwas prepared according to the general methods of Example 59 using1-(aminomethyl)cyclobutanol in lieu of 1-(aminomethyl)cyclohexanol inPart A and trimethylorthoacetate in lieu of trimethylorthobutyrate inPart D. The crude product was purified by HPFC eluting with a gradientof 0-50% CMA in chloroform, triturated with 1N sodium hydroxide, andthen it was suspended in water (70 mL). Concentrated hydrochloric acid(1.0 mL) was added and the mixture was heated to 90° C. The hot solutionwas made basic with solid sodium bicarbonate and then allowed to cool. Aprecipitate was isolated by filtration, washed well with water, and thendried to provide pure product as a white powder, mp>250.0° C. Anal.Calcd for C₁₄H₂₀N₄O C, 64.59; H, 7.74; N, 21.52. Found: C, 64.57; H,7.81; N, 21.61.

Example 1071-[(4-Amino-2-ethoxymethyl-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl]cyclobutanol

1-[(4-Amino-2-ethoxymethyl-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl]cyclobutanolwas prepared according to the general methods of Example 93 using1-[(3-amino-2-dibenzylamino-5,6-dimethylpyridin-4-ylamino)methyl]cyclobutanolin lieu of1-[(3-amino-2-dibenzylamino-5,6-dimethylpyridin-4-ylamino)methyl]cyclohexanolin Part A. The crude product was purified by HPFC eluting with agradient of 0-50% CMA in chloroform and then suspended in water (70 mL).Concentrated hydrochloric acid (2 mL) was added and the mixture washeated to 90° C. The hot solution was made basic (pH 8) with solidsodium bicarbonate. Sodium hydroxide (1N) was added until the solutionbecame cloudy. The solution was allowed to cool to ambient temperature.A precipitate was isolated by filtration, washed well with water, andthen dried to provide pure product as a white powder, mp 190.0-191.0° C.Anal. Calcd for C₁₆H₂₄N₄O₂ C, 63.13; H, 7.95; N, 18.41. Found: C, 63.01;H, 8.04; N, 18.48.

Example 1081-[(4-Amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]cyclobutanol

1-[(4-Amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]cyclobutanolwas prepared according to the general methods of Example 57 using4-chloro-3-nitroquinoline in lieu of 4-chloro-3-nitronaphthyridine and1-(aminomethyl)cyclobutanol in lieu of 1-(aminomethyl)cyclohexanol inPart A and trimethylorthoacetate in lieu of trimethylorthobutyrate inPart C. The crude product was triturated sequentially with ethylacetate, hot chloroform, and acetonitrile, purified by HPFC eluting witha gradient of 0-40% CMA in chloroform, and then suspended in water (100mL). Concentrated hydrochloric acid (2 mL) was added and the mixture washeated to 90° C. The hot solution was made basic (pH 10) with solidsodium bicarbonate. The solution was allowed to cool to ambienttemperature. A precipitate was isolated by filtration, washed well withwater, and then dried to provide pure product as a white powder,mp>250.0° C. Anal. Calcd for C₁₆H₁₈N₄O C, 68.06; H, 6.43; N, 19.84.Found: C, 67.99; H, 6.54; N, 19.81.

Example 1091-[(4-Amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]cyclobutanol

Part A

1-[(4-Chloro-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]cyclobutanolwas prepared according to the general methods of Example 57 using2,4-dichloro-3-nitroquinoline in lieu of 4-chloro-3-nitronaphthyridineand 1-(aminomethyl)cyclobutanol in lieu of 1-(aminomethyl)cyclohexanolin Part A.

Part B

1-[(4-Chloro-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]cyclobutanol(1.56 g) was combined with a solution of ammonia in methanol (23 mL).The mixture was heated at 150° C. in a pressure vessel for 2 days. Aportion of the solvent was removed under vacuum and then the mixture wasdiluted with additional methanol. A solid was isolated by filtration,washed with methanol, triturated with acetonitrile, and then dried. Thematerial was suspended in water (70 mL). Concentrated hydrochloric acid(1.4 mL) was added and the mixture was heated at 90° C. for 30 minutes.The hot solution was neutralized with solid sodium bicarbonate. Thesolution was allowed to cool to ambient temperature. A precipitate wasisolated by filtration, washed well with water, and then dried toprovide1-[(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]cyclobutanolas a white powder, mp 228.0-229.0° C. Anal. Calcd for C₁₈H₂₂N₄O C,69.65; H, 7.14; N, 18.05. Found: C, 69.36; H, 7.24; N, 18.03.

Example 1101-[(4-Amino-1H-imidazo[4,5-c]quinolin-1-yl)methyl]cyclobutanol

1-[(4-Amino-1H-imidazo[4,5-c]quinolin-1-yl)methyl]cyclobutanol wasprepared according to the general methods of Example 109 usingtrimethylorthoformate in lieu of trimethylorthobutyrate. The crudeproduct was triturated with refluxing 1:1 ethyl acetate:acetonitrile,purified by HPFC eluting with a gradient of 0-45% CMA in chloroform,triturated with 1:1 water:acetonitrile, and then suspended in water (80mL). Concentrated hydrochloric acid (1.5 mL) was added and the mixturewas heated at 90° C. for 10 minutes. The hot solution was made basic (pH9) with solid sodium bicarbonate. The solution was allowed to cool toambient temperature. A precipitate was isolated by filtration, washedwell with water, and then dried. This material was triturated withsodium hydroxide (15 mL of 1N), isolated by filtration, washed well withwater, and then dried to provide pure product as a white powder,mp>250.0° C. Anal. Calcd for C₁₅H₁₆N₄O C, 67.15; H, 6.01; N, 20.88.Found: C, 67.06; H, 6.01; N, 21.09.

Example 1111-[(4-Amino-2-hydroxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]cyclobutanol

Part A

1-[(4-Amino-2-chloromethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]cyclobutanolwas prepared according to the general methods of Example 103 except thatchloroacetyl chloride was used in lieu of ethoxyacetyl chloride andtriethylamine was used in lieu of sodium hydroxide.

Part B

1-[(4-Amino-2-chloromethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]cyclobutanolwas converted to1-[(4-amino-2-hydroxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]cyclobutanolaccording to the general methods of Parts D and E of Example 62. Thecrude product was triturated with 1:1 ethyl acetate:methanol, dried, andthen suspended in water (90 mL). Concentrated hydrochloric acid (1.5 mL)was added and the mixture was heated at 90° C. for 3 minutes. Themixture was allowed to cool to ambient temperature and was then madebasic with solid sodium bicarbonate. A solid was isolated by filtration,rinsed well with water, dried, and then purified by HPFC eluting with agradient of 0-60% CMA in chloroform. The resulting solid was trituratedwith acetonitrile, dried, and then suspended in water (80 mL).Concentrated hydrochloric acid (1.5 mL) was added and the mixture washeated at 90° C. for 10 minutes. The hot solution was made basic (pH 9)with solid sodium bicarbonate. The solution was allowed to cool toambient temperature. A precipitate was isolated by filtration, washedwell with water, and then dried to provide pure product as a whitepowder, mp>250.0° C. Anal. Calcd for C₁₆H₁₈N₄O₂ C, 64.41; H, 6.08; N,18.78. Found: C, 64.30; H, 6.10; N, 18.54.

Example 1121-[(4-Amino-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl]tetrahydro-2H-pyran-4-ol

Part A

Under a nitrogen atmosphere 2,4-dichloro-5,6-dimethyl-3-nitropyridine(25 g, 113 mmol) was added to a solution of4-(aminomethyl)tetrahydro-2H-pyran-4-ol (17 g, 130 mmol) in DMF (375mL). Triethylamine (18 mL, 130 mmol) was added slowly and the reactionmixture was stirred at ambient temperature over the weekend. Thereaction mixture was concentrated under reduced pressure and the residuewas partitioned between ethyl acetate (700 mL) and saturated aqueoussodium bicarbonate (100 mL). The organic layer was washed with water(3×100 mL) and brine (50 mL), dried over magnesium sulfate, filtered,and then concentrated under reduced pressure to provide an orange solid.This material was triturated with ethyl acetate to provide 6.38 g of4-{[(2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)amino]methyl}tetrahydro-2H-pyran-4-olas a yellow solid. An additional 4.36 g of product was recovered fromthe mother liquor.

Part B

4-{[(2-Chloro-5,6-dimethyl-3-nitropyridin-4-yl)amino]methyl}tetrahydro-2H-pyran-4-ol(8.74 g, 27.7 mmol), 10% platinum on carbon (874 mg), and ethyl acetate(185 mL) were combined and placed under hydrogen pressure (50 psi,3.4×10⁵ Pa) on a Parr apparatus for 4 hours. The reaction mixture wasfiltered through a layer of CELITE filter aid and the filter cake waswashed with 1:1 ethyl acetate:methanol. The filtrate was concentratedunder reduced pressure to provide crude4-{[(3-amino-2-chloro-5,6-dimethylpyridin-4-yl)amino]methyl}tetrahydro-2H-pyran-4-ol.

Part C

Under a nitrogen atmosphere a mixture of the material from Part B,trimethylorthoacetate (1.94 mL, 15.2 mmol), pyridine hydrochloride (240mg), and toluene was heated at reflux overnight. The reaction mixturewas allowed to cool to ambient temperature. A precipitate was isolatedby filtration to provide 2.35 g of1-[(4-chloro-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl]tetrahydro-2H-pyran-4-olas a white solid. An additional 1.15 g was isolated from the motherliquor. A portion was recrystallized from ethyl acetate hexanes toprovide pure product as a white powder, mp 217.0-218.0° C. Anal. Calcdfor C₁₅H₂₀ClN₃O₂ C, 58.16; H, 6.51; N, 13.56; Cl, 11.44. Found: C,58.14; H, 6.37; N, 13.31; Cl, 11.30.

Part D

1-[(4-Chloro-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl]tetrahydro-2H-pyran-4-ol(1.00 g, 3.23 mmol), benzylamine (3.53 mL, 32.3 mmol), pyridinehydrochloride (2.52 g, 16.2 mmol) and 2,2,2-trifluoroethanol (10 mL)were combined in a process vial and heated in a microwave at 160° for2.5 hours. The reaction mixture was concentrated under reduced pressure.The residue was dissolved in chloroform (200 mL), washed with saturatedaqueous sodium bicarbonate (3×50 mL) and brine (30 mL), dried overmagnesium sulfate, filtered, and then concentrated under reducedpressure to provide a yellow solid. This material was triturated withacetonitrile to provide 1.14 g of1-{[4-(benzylamino)-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-1-yl]methyl}tetrahydro-2H-pyran-4-olas a white solid.

Part E

The benzyl group was removed from the material from Part D according tothe general method of Part E of Example 59. The crude product wastriturated with acetonitrile and dried to provide a white solid. Thismaterial was dissolved in chloroform (200 mL), washed with saturatedaqueous sodium bicarbonate (2×40 mL) and brine (30 mL), dried oversodium sulfate, filtered, and then concentrated under reduced pressure.The residue was triturated with acetonitrile and dried to provide1-[(4-amino-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl]tetrahydro-2H-pyran-4-olas a white powder, mp>250.0° C. Anal. Calcd for C₁₅H₂₂N₄O₂ C, 62.05; H,7.64; N, 19.30. Found: C, 61.89; H, 7.77; N, 19.34.

Example 1131-[(2,6,7-Trimethyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl]tetrahydro-2H-pyran-4-ol

A mixture of1-[(4-chloro-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl]tetrahydro-2H-pyran-4-ol(1.0 g), 10% palladium on carbon (200 mg), and ethanol (16 mL) werecombined and placed under hydrogen pressure (50 psi, 3.4×10⁵ Pa) on aParr apparatus for 6 days. The reaction mixture was filtered through alayer of CELITE filter aid and the filter cake was washed with methanol.The filtrate was concentrated under reduced pressure. The residue wastriturated with acetonitrile to provide a solid. This material wasdissolved in dichloromethane (100 mL) and washed with sodium hydroxide(1N, 2×30 mL) and brine, dried over sodium sulfate, filtered, and thenconcentrated under reduced pressure. The residue was triturated withacetonitrile to provide1-[(2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl]tetrahydro-2H-pyran-4-olas a white powder, mp 246.0-248.0° C. Anal. Calcd for C₁₅H₂₁N₃O₂ C,65.43; H, 7.69; N, 15.26. Found: C, 65.53; H, 7.79; N, 15.42.

Example 1141-[(4-Amino-2-ethoxymethyl-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl]tetrahydro-2H-pyran-4-ol

Part A

Under a nitrogen atmosphere ethoxyacetyl chloride (2.26 g, 16.6 mmol)was added dropwise to a chilled (0° C.) suspension of4-{[(3-amino-2-chloro-5,6-dimethylpyridin-4-yl)amino]methyl}tetrahydro-2H-pyran-4-ol(3.96 g) in dichloromethane (140 mL). The reaction mixture was stirredat ambient temperature overnight. The reaction mixture was cooled to 0°C., more ethoxyacetyl chloride (0.3 mL) was added, and the reactionmixture was stirred at ambient temperature for an additional 4 hours.The reaction mixture was concentrated under reduced pressure to providecrudeN-(2-chloro-4-{[(4-hydroxytetrahydro-2H-pyran-4-yl)methyl]amino}-5,6-dimethylpyridin-3-yl)-2-ethoxyacetamide.

Part B

Sodium hydroxide (1.11 g, 27.7 mmol) was added to a suspension of thematerial from Part A in ethanol (138 mL). The reaction mixture washeated at reflux for 1.5 hours and then concentrated under reducedpressure. The residue was dissolved in dichloromethane (400 mL), washedwith water (2×80 mL) and brine (40 mL), dried over magnesium sulfate,filtered, and then concentrated under reduced pressure to provide 4.46 gof a yellow solid. This material was triturated with ethyl acetate andthen recrystallized from ethyl acetate/hexanes to provide1-[(4-chloro-2-ethoxymethyl-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl]tetrahydro-2H-pyran-4-olas a white powder, mp 151.0-152.0° C. Anal. Calcd for C₁₇H₂₄ClN₃O₃ C,57.70; H, 6.84; N, 11.88; Cl, 10.02. Found: C, 57.57; H, 6.87; N, 11.68;Cl, 10.00.

Part C

1-[(4-Chloro-2-ethoxymethyl-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl]tetrahydro-2H-pyran-4-ol(1.4 g) was converted to1-[(4-amino-2-ethoxymethyl-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl]tetrahydro-2H-pyran-4-olaccording to the general methods of Parts D and E of Example 112. Thecrude product was dissolved in chloroform (200 mL) and methanol (10 mL),washed with saturated aqueous sodium bicarbonate (2×40 mL) and brine (30mL), dried over sodium sulfate, filtered, and then concentrated underreduced pressure. The residue was triturated with acetonitrile and driedto provide pure product as a white powder, mp 197.0-198.0° C. Anal.Calcd for C₁₇H₂₆N₄O₃ C, 61.06; H, 7.84; N, 16.75. Found: C, 60.91; H,8.18; N, 16.87.

Example 1151-[(2-Ethoxymethyl-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl]tetrahydro-2H-pyran-4-ol

A mixture of1-[(4-chloro-2-ethoxymethyl-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl]tetrahydro-2H-pyran-4-ol(1.0 g), 10% palladium on carbon (200 mg), and ethanol (16 mL) werecombined and placed under hydrogen pressure (50 psi, 3.4×10⁵ Pa) on aParr apparatus for 1 week. The reaction mixture was filtered through alayer of CELITE filter aid and the filter cake was washed with methanol.The filtrate was concentrated under reduced pressure. The residue wasdissolved in dichloromethane (150 mL) and washed with sodium hydroxide(1N, 2×20 mL) and brine (20 mL), dried over sodium sulfate, filtered,and then concentrated under reduced pressure. The residue was trituratedwith acetonitrile and then recrystallized from acetonitrile to provide1-[(2-ethoxymethyl-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl]tetrahydro-2H-pyran-4-olas a white powder, mp 144.0-145.0° C. Anal. Calcd for C₁₇H₂₅N₃O₃ C,63.93; H, 7.89; N, 13.16. Found: C, 63.68; H, 7.89; N, 13.04.

Example 1164-[(4-Amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]tetrahydro-2H-thiopyran-4-ol

Part A

Under a nitrogen atmosphere sodium methoxide (1.03 mL of 25 wt % inmethanol, 4.51 mmol) was added dropwise to a solution oftetrahydro-4H-thiopyran-4-one (10.48 g, 90.20 mol) and nitromethane(7.33 mL, 135.3 mmol) in ethanol (6 mL). The reaction mixture wasstirred at ambient temperature for 5 days and then concentrated underreduced pressure. The residue was partitioned between chloroform (400mL) and water (60 mL). The aqueous was extracted with chloroform (5×100mL). The combined organics were dried over magnesium sulfate, filtered,and then concentrated under reduced pressure. The residue was purifiedby HPFC eluting with a gradient of 3-35% ethyl acetate in hexanes toprovide 10.23 g of 4-(nitromethyl)tetrahydro-2H-thiopyran-4-ol.

Part B

The material from Part B, 20% palladium hydroxide on carbon (2.0 g), andethanol (165 mL) were combined and placed under hydrogen pressure (50psi, 3.4×10⁵ Pa) on a Parr apparatus for 1 week. The reaction mixturewas filtered through a layer of CELITE filter aid and the filter cakewas washed with methanol. The filtrate was concentrated under reducedpressure. The residue was dried under high vacuum to provide 8.54 g of4-(aminomethyl)tetrahydro-2H-thiopyran-4-ol as a white semi-solid.

Part C

Under a nitrogen atmosphere triethylamine (3.91 mL, 28.0 mmol) was addedto a chilled (0° C.) solution of 2,4-dichloro-3-nitroquinoline (7.22 g,26.7 mmol) in dichloromethane (100 mL). A solution of4-(aminomethyl)tetrahydro-2H-thiopyran-4-ol (4.12 g, 28.0 mmol) indichloromethane (30 mL) was added dropwise. The reaction mixture wasstirred at ambient temperature overnight and then concentrated underreduced pressure. The orange residue was combined with saturated aqueoussodium bicarbonate (50 mL) and ethyl acetate (40 mL), sonicated for 10minutes, and then filtered. The isolated solid was washed extensivelywith water and then dried to provide 5.63 g of4-{[(2-chloro-3-nitroquinolin-4-yl)amino]methyl}tetrahydro-2H-thiopyran-4-olas a yellow solid.

Part D

A portion (1.00 g) of the material from Part C, 5% platinum on carbon(200 mg g) and ethyl acetate (28 mL) were combined and placed underhydrogen pressure (50 psi, 3.4×10⁵ Pa) on a Parr apparatus overnight.The reaction mixture was filtered through a layer of CELITE filter aidand the filter cake was washed with methanol. The filtrate wasconcentrated under reduced pressure to provide4-{[(3-amino-2-chloroquinolin-4-yl)amino]methyl}tetrahydro-2H-thiopyran-4-olas an off-white solid.

Part E

Under a nitrogen atmosphere butyryl chloride (322 μL, 3.11 mmol) wasadded dropwise was added to a suspension of4-{[(3-amino-2-chloroquinolin-4-yl)amino]methyl}tetrahydro-2H-thiopyran-4-ol(0.92 g, 2.83 mmol) in dichloromethane (28 mL). After 2 hourstriethylamine (0.79 mL, 5.66 mol) was added and the reaction mixture wasstirred for 2 hours. More butyryl chloride (0.2 mL) and triethylamine(0.30 mL) were added. The reaction mixture was stirred for an additionalhour and then diluted with saturated aqueous sodium bicarbonate (50 mL)and extracted with dichloromethane (3×60 mL). The combined organics werewashed with saturated aqueous sodium bicarbonate (40 mL) and brine (30mL), dried over sodium sulfate, filtered, and then concentrated underreduced pressure to provideN-(2-chloro-4-{[(4-hydroxytetrahydro-2Hthiopyran-4-yl)methyl]amino}quinolin-3-yl)butanamideas an off-white solid.

Part F

The material from Part E was combined with a solution of ammonia inmethanol (17 mL of 7N) in a pressure vessel. The vessel was sealed andheated at 150° C. for 24 hours. A solid was isolated by filtration andrinsed with methanol to provide 0.60 g of yellow needles. This materialwas combined with acetonitrile and sonicated. A white solid was isolatedby filtration, rinsed with acetonitrile, and dried under high vacuum at120° C. to provide 538 mg of4-[(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]tetrahydro-2H-thiopyran-4-olas a white powder, mp 243.0-244.0° C. Anal. Calcd for C₁₉H₂₄N₄OS C,64.02; H, 6.79; N, 15.72. Found: C, 64.20; H, 6.99; N, 15.52.

Example 1174-[(4-Amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]tetrahydro-2H-thiopyran-4-ol1,1-dioxide

Under a nitrogen atmosphere 3-chloroperbenzoic acid (1.20 g of 70%, 4.89mmol) was added to a cooled (0° C.) solution of4-[(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]tetrahydro-2H-thiopyran-4-ol(0.79 g, 2.22 mmol) in chloroform (22 mL) and methanol (22 mL). Thereaction mixture was warmed to ambient temperature. The reaction mixturewas treated with additional 3-chloroperbenzoic acid (0.8 g total) andstirred until analysis by LC-MS (liquid chromatography-massspectroscopy) indicated that the reaction was complete. The reactionmixture was diluted with saturated aqueous sodium carbonate (50 mL) andthen extracted with chloroform (4×50 mL). The combined organics werewashed with brine (20 mL), dried over sodium sulfate, filtered, and thenconcentrated under reduced pressure to provide 1.1 g of a brown solid.This material was purified by HPFC eluting with a gradient of 0-30% CMAin chloroform to give 0.43 g of a solid. This material was trituratedwith acetonitrile and dried under high vacuum at 130° C. to provide 266mg of4-[(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]tetrahydro-2H-thiopyran-4-ol1,1-dioxide as a tan powder, mp>250.0° C. Anal. Calcd for C₁₉H₂₄N₄O₃S C,58.74; H, 6.23; N, 14.42. Found: C, 58.71; H, 6.14; N, 14.42.

Example 1184-[(4-Amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]tetrahydro-2H-thiopyran-4-ol

4-[(4-Amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]tetrahydro-2H-thiopyran-4-olwas prepared according to the general methods of Example 116 usingpropionyl chloride in lieu of butyryl chloride in Part E. The crudeproduct was recrystallized from methanol/chloroform, isolated byfiltration, rinsed with chloroform and methanol, and then dried underhigh vacuum at 130° C. to provide pure product as a white powder,mp>250.0° C. Anal. Calcd for C₁₈H₂₂N₄OS.0.2H₂O C, 62.47; H, 6.52; N,16.19. Found: C, 62.47; H, 6.37; N, 16.09.

Example 1194-[(4-Amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]tetrahydro-2H-thiopyran-4-ol1,1 dioxide

4-[(4-Amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]tetrahydro-2H-thiopyran-4-ol(900 mg) was oxidized according to the method of Example 117. The crudeproduct (1.1 g of a brown solid) was triturated with acetonitrile, andthen purified by HPFC eluting with a gradient of 0-40% CMA in chloroformto provide 1.1 g of a brown solid. This material was triturated withacetonitrile and dried under high vacuum at 120° C. to provide 330 mg of4-[(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]tetrahydro-2H-thiopyran-4-ol1,1 dioxide as a white powder, mp>250.0° C. Anal. Calcd for C₁₈H₂₂N₄O₃SC, 57.74; H, 5.92; N, 14.96. Found: C, 57.51; H, 5.97; N, 15.13.

Example 120 tert-Butyl4-[(4-amino-2-ethyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]-4-hydroxypiperidine-1-carboxylate

Part A

Under a nitrogen atmosphere a solution of tert-butyl4-(aminomethyl)-4-hydroxypiperidine-1-carboxylate (38.9 g, 169 mmol,prepared according to Parts A and B of Example 4) in dichloromethane(420 mL) was cooled to 0° C. Triethylamine (23.6 mL, 169 mmol) was addedfollowed by the portionwise addition of 4-chloro-3-nitronaphthyridine(30.8 g, 147 mmol). The reaction mixture was stirred at ambienttemperature overnight and then diluted with saturated aqueous sodiumbicarbonate (200 mL). The layers were separated and the aqueous wasextracted with dichloromethane (3×100 mL). The combined organics wereconcentrated under reduced pressure to provide a dark yellow solid. Thismaterial was triturated with saturated aqueous sodium bicarbonate,isolated by filtration, rinsed well with water, and then dried in avacuum oven at 70° C. overnight to provide 58.85 g of tert-butyl4-hydroxy-4-{[(3-nitro[1,5]naphthyridin-4-yl)amino]methyl}piperidine-1-carboxylateas a yellow solid.

Part B

The material from Part A, 5% platinum on carbon (5.89 g), and ethylacetate (500 mL) were combined and placed under hydrogen pressure (30psi, 2.1×10⁵ Pa) on a Parr apparatus for 2.5 hours. The reaction mixturewas filtered through a layer of CELITE filter aid and the filter cakewas washed with ethyl acetate. The filtrate was concentrated underreduced pressure to provide tert-butyl4-hydroxy-4-{[(3-amino[1,5]naphthyridin-4-yl)amino]methyl}piperidine-1-carboxylate.

Part C

Under a nitrogen atmosphere a portion (27.24 g, 72.9 mmol) of thematerial from Part B was combined with toluene (300 mL),triethylorthopropionate (16.1 mL, 80.2 mmol), and pyridine hydrochloride(1.3 g, 10.9 mmol). The reaction mixture was stirred at reflux for 3hours, allowed to cool to ambient temperature, and then concentratedunder reduced pressure. The residue was dried under high vacuum,dissolved in chloroform (500 mL), washed with saturated aqueous sodiumbicarbonate (2×80 mL) and brine (40 mL), dried over magnesium sulfate,filtered, and then concentrated under reduced pressure to provide 34 gof a yellow solid. This material was triturated with ethylacetate/hexanes, isolated by filtration, rinsed with hexanes, and thendried to provide tert-butyl4-[(2-ethyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]-4-hydroxypiperidine-1-carboxylate.A portion (2 g) of this material was recrystallized from ethylacetate/hexanes, isolated by filtration, rinsed with hexanes, and thendried under vacuum at 120° C. to provide 1.1 g of pure product as awhite powder, mp 155.0-156.0° C. Anal. Calcd for C₂₂H₂₉N₅O₃ C, 64.21; H,7.10; N, 17.02. Found: C, 63.99; H, 6.88; N, 16.90.

Part D

Under a nitrogen atmosphere, 3-chloroperoxybenzoic acid (13.8 g of 70%,56.0 mmol) was added to a solution of tert-butyl4-[(2-ethyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]-4-hydroxypiperidine-1-carboxylate(16.5 g, 40.0 mmol) in chloroform (160 mL). After 1.5 hours the reactionmixture was concentrated under reduced pressure to provide a yellowfoam. Under a nitrogen atmosphere this material was dissolved inmethanol (160 mL) and then cooled to 0° C. Ammonium hydroxide (13.3 mL,200 mmol) was slowly added followed by the dropwise addition ofbenzenesulfonyl chloride (10.7 mL, 84.0 mmol). The reaction mixture wasstirred at 0° C. for 1.5 hours and then concentrated under reducedpressure. The residue was partitioned between chloroform (400 mL) andsaturated aqueous sodium bicarbonate (50 mL). The organic was washedwith saturated aqueous sodium bicarbonate (50 mL) and brine (30 mL),dried over magnesium sulfate, filtered, and then concentrated underreduced pressure. The residue was triturated with ethyl acetate toprovide a yellow solid. This material was triturated with saturatedaqueous sodium carbonate to provide 7.2 g of a yellow solid. A portion(1.2 g) of this material was triturated twice with acetonitrile,isolated by filtration, and dried under vacuum at 120° C. to provide 736mg of tert-butyl4-[(4-amino-2-ethyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]-4-hydroxypiperidine-1-carboxylateas a white powder, mp 233.0-235.0° C. Anal. Calcd for C₂₂H₃₀N₆O₃ C,61.95; H, 7.09; N, 19.70. Found: C, 61.78; H, 7.15; N, 19.51.

Example 1214-[(4-Amino-2-ethyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]piperidin-4-ol

Part A

Under a nitrogen atmosphere a mixture of tert-butyl4-[(4-amino-2-ethyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]-4-hydroxypiperidine-1-carboxylate(6.00 g), aqueous hydrochloric acid (14 mL of 6M), and ethanol (56 mL)was heated at 50° C. overnight. The reaction mixture was concentratedunder reduced pressure. The residue was concentrated from methanol 3times, triturated with acetonitrile, isolated by filtration, washed withacetonitrile, and then dried under high vacuum to provide 5.55 g of4-[(4-amino-2-ethyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]piperidin-4-oldihydrochloride as a tan powder.

Part B

A mixture of4-[(4-amino-2-ethyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]piperidin-4-oldihydrochloride (0.80 g) and 1N sodium hydroxide (8 mL) was sonicatedfor 2 minutes. A solid was isolated by filtration, washed with water,and dried. This procedure was repeated and the material was dried underhigh vacuum at 120° C. to provide 0.61 g of4-[(4-amino-2-ethyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]piperidin-4-olas a tan powder, mp 232.0-233.0° C. Anal. Calcd for C₁₇H₂₂N₆O C, 62.56;H, 6.79; N, 25.75. Found: C, 62.43; H, 7.04; N, 25.78.

Example 1224-[(4-Amino-2-ethyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]-1-(morpholin-4-ylcarbonyl)piperidin-4-ol

Under a nitrogen atmosphere triethylamine (1.39 mL, 10.0 mmol) was addedto a suspension of4-[(4-amino-2-ethyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]piperidin-4-oldihydrochloride (1.00 g, 2.50 mmol) in dichloromethane (25 mL). Themixture was cooled to −5° C. 4-Morpholinecarbonyl chloride (292 μL, 2.50mmol) was added and the reaction mixture was allowed to slowly warm toambient temperature. The reaction mixture was stirred at ambienttemperature for 2 days and then at 30° C. for 2 days. More4-morpholinecarbonyl chloride (30 μL) was added and the reaction mixturewas stirred at 30° C. for 5 days. The reaction mixture was concentratedunder reduced pressure. The residue was partitioned between chloroform(150 mL) and saturated aqueous sodium carbonate (30 mL). The organic waswashed with saturated aqueous sodium carbonate (20 mL) and brine (20mL), dried over sodium sulfate, filtered, and then concentrated underreduced pressure to provide an off white solid. This material wastriturated with acetonitrile, recrystallized from chloroform/hexanes,isolated by filtration, washed with hexanes, and dried under high vacuumat 130° C. to provide 0.97 g of4-[(4-amino-2-ethyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]-1-(morpholin-4-ylcarbonyl)piperidin-4-olas a white powder, mp>255.0° C. Anal. Calcd for C₂₂H₂₉N₇O₃.0.25H₂O C,59.51; H, 6.70; N, 22.08. Found: C, 59.32; H, 6.36; N, 22.00.

Example 1234-[(4-Amino-2-ethyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]-1-(methylsulfonyl)piperidin-4-ol

Under a nitrogen atmosphere triethylamine (1.12 mL, 8.06 mmol) was addedto a suspension of4-[(4-amino-2-ethyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]piperidin-4-oldihydrochloride (1.04 g, 2.60 mmol) in chloroform (26 mL).Methanesulfonic anhydride (0.50 g, 2.86 mmol) was added and the reactionmixture was stirred at ambient temperature. After 1.5 hours moremethanesulfonic anhydride (0.25 g) was added and a solution wasobtained. On two successive days more methanesulfonic anhydride (0.50 g)and triethylamine (360 μL) were added. The reaction mixture was stirredfor 2 hours after the second addition and then concentrated underreduced pressure. The residue was triturated with saturated aqueoussodium bicarbonate, isolated by filtration, washed with water,triturated with hot chloroform, isolated by filtration, washed withchloroform and hexanes, dried, triturated with acetonitrile, sonicated,isolated by filtration, and then dried under high vacuum at 130° C. toprovide4-[(4-amino-2-ethyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]-1-(methylsulfonyl)piperidin-4-olas a white powder, mp>255.0° C. Anal. Calcd for C₁₈H₂₄N₆O₃S C, 53.45; H,5.98; N, 20.78. Found: C, 53.55; H, 5.71; N, 20.75.

Example 124 tert-butyl4-[(4-Amino-2-methyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]-4-hydroxypiperidine-1-carboxylate

Part A

tert-Butyl4-[(2-methyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]-4-hydroxypiperidine-1-carboxylatewas prepared according to the methods of Parts A through C of Example120 using trimethylorthoacetate in lieu of triethylorthopropionate inPart C. The product was provided as a white powder, mp 175.0-176.0° C.Anal. Calcd for C₂₁H₂₇N₅O₃ C, 63.46; H, 6.85; N, 17.62. Found: C, 63.30;H, 6.77; N, 17.53.

Part B

tert-Butyl4-[(2-methyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]-4-hydroxypiperidine-1-carboxylate(15.9 g) was oxidized and then aminated according to the methods of PartD of Example 120. The crude product was triturated with ethyl acetate toprovide 5.8 g of a yellow solid. A portion (0.8 g) of this material wastwice triturated with acetonitrile, isolated by filtration, and driedunder high vacuum at 120° C. to provide tert-butyl4-[(4-amino-2-methyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]-4-hydroxypiperidine-1-carboxylateas a white powder, mp 233.0-235.0° C. Anal. Calcd for C₂₁H₂₈N₆O₃.0.5H₂OC, 59.84; H, 6.93; N, 19.94. Found: C, 59.96; H, 6.78; N, 19.59.

Example 1254-[(4-Amino-2-methyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]piperidin-4-ol

Part A

Under a nitrogen atmosphere a mixture of tert-butyl4-[(4-amino-m2-ethyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]-4-hydroxypiperidine-1-carboxylate(5.00 g), aqueous hydrochloric acid (12 mL of 6M), and ethanol (48 mL)was heated at 50° C. overnight. The reaction mixture was concentratedunder reduced pressure. The residue was concentrated from methanol 3times, triturated with acetonitrile, isolated by filtration, washed withacetonitrile, and then dried under high vacuum to provide 4.67 g of4-[(4-amino-2-methyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]piperidin-4-oldihydrochloride as a pale yellow solid.

Part B

A mixture of4-[(4-amino-2-methyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]piperidin-4-oldihydrochloride (0.80 g) and 1N sodium hydroxide (8 mL) was sonicatedfor 2 minutes. A solid was isolated by filtration, washed with water,and dried under high vacuum at 100° C. to provide 0.50 g of4-[(4-amino-2-methyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]piperidin-4-olas a yellow powder, mp>260.0° C. Anal. Calcd for C₁₆H₂₀N₆O C, 61.52; H,6.45; N, 26.90. Found: C, 61.23; H, 6.39; N, 26.92.

Example 1264-[(4-Amino-2-methyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]-1-(morpholin-4-ylcarbonyl)piperidin-4-ol

4-[(4-Amino-2-methyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]-1-(morpholin-4-ylcarbonyl)piperidin-4-olwas prepared and purified according to the general method of Example 122using4-[(4-amino-2-methyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]piperidin-4-oldihydrochloride in lieu of4-[(4-amino-2-ethyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]piperidin-4-oldihydrochloride. The product was provided as a white powder, mp245.0-248.0° C. Anal. Calcd for C₂₁H₂₇N₇O₃ C, 59.28; H, 6.40; N, 23.04.Found: C, 58.98; H, 6.67; N, 22.91.

Example 1274-[(4-Amino-2-methyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]-1-(methylsulfonyl)piperidin-4-ol

4-[(4-Amino-2-methyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]-1-(methylsulfonyl)piperidin-4-olwas prepared and purified according to the general method of Example 123using4-[(4-amino-2-methyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]piperidin-4-oldihydrochloride in lieu of4-[(4-amino-2-ethyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]piperidin-4-oldihydrochloride. The product was provided as a white powder, mp>255.0°C. Anal. Calcd for C₁₇H₂₂N₆O₃S C, 52.29; H, 5.68; N, 21.52. Found: C,52.14; H, 5.39; N, 21.38.

Example 1281-[(1-Aminocyclohexyl)methyl]-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine

Part A

Tert-butyl1-[(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]cyclohexylcarbamate(3.80 g, Example 54 Parts A through F) was oxidized and aminatedaccording to the general methods of Part F of Example 10 to provide 2.46g of tert-butyl1-[(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]cyclohexylcarbamateas a light tan frothy solid, mp 82.0-92.0° C.

Part B

Under a nitrogen atmosphere a mixture of the material from Part A,hydrochloric acid (25 mL of 2.7M in ethanol), and ethanol (50 mL) washeated at reflux for 2 hours. The reaction mixture was diluted withisopropanol. A solid was isolated by filtration and then partitionedbetween dichloromethane (100 mL) and 5% sodium carbonate (100 mL). Theaqueous layer was extracted with dichloromethane (2×100 mL). Theorganics were combined, dried over magnesium sulfate, filtered, and thenconcentrated under reduced pressure to provide a light yellow oil. Thismaterial was purified by column chromatography (silica gel eluting with90/10 dichloromethane/methanol) to provide a clear oil. The oil wasdissolved in methanol and then concentrated under reduced pressure toprovide 1.10 g of1-[(1-aminocyclohexyl)methyl]-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amineas a white frothy solid, mp 166-168° C. ¹H NMR (300 MHz, CDCl₃) δ 8.26(m, 1H), 7.80 (m, 1H), 7.49 (ddd, J=8.3, 6.9, 1.4 Hz, 1H), 7.30 (ddd,J=8.3, 6.9, 1.4 Hz, 1H), 5.45 (br s, 2H), 5.02 (br s, 2H), 4.66 (br s,2H), 3.57 (q, J=7.0 Hz, 2H), 1.70-1.37 (m, 10H), 1.29-0.94 (m, 2H), 1.23(t, J=7.0 Hz, 3H); MS (APCI) m/z 354 (M+H)⁺; Anal. Calcd forC₂₀H₂₇N₅O.0.25 H₂O: C, 67.11; H, 7.74; N, 19.56. Found: C, 67.06; H,7.74; N, 19.36.

Example 129 Ethyl1-[(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]cyclohexylcarbamate

Part A

Under a nitrogen atmosphere a mixture of1-[(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]cyclohexylamine(2.00 g, 5.91 mmol, Example 54 Parts A through G) and THF (40 mL) wascooled in an ice bath. Sodium hydroxide (0.24 g, 5.97 mmol, in 3 mL ofwater) was added dropwise followed by diethylpyrocarbonate (0.87 mL,5.91 mmol). After two days an additional 0.5 eq of both sodium hydroxideand diethylpyrocarbonate were added. After 5 days the reaction mixturewas concentrated under reduced pressure. The residue was partitionedbetween water (100 mL) and dichloromethane (100 mL). The organic wasdried over magnesium sulfate, filtered, and then concentrated underreduced pressure to provide an oil. This material was purified by columnchromatography (silica gel eluting with 95/5 ethyl acetate/methanol) toprovide 1.89 g of ethyl1-[(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]cyclohexylcarbamateas a clear oil.

Part B

The material from Part A was oxidized and then aminated according to thegeneral methods of Part F of Example 9. Crude product (0.25 g of anamber oil) was dissolved in hot ethyl acetate/hexanes and the solutionwas cooled to provide a solid. This material was dissolved in methanoland then concentrated under reduced pressure to provide 67 mg of ethyl1-[(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]cyclohexylcarbamateas a white frothy solid, mp 95-100° C. ¹H NMR (300 MHz, CDCl₃) δ 8.24(m, 1H), 7.80 (dd, J=8.3, 1.0 Hz, 1H), 7.50 (ddd, J=8.3, 7.0, 1.3 Hz,1H), 7.31 (ddd, J=8.3, 7.0, 1.3 Hz, 1H), 5.45 (br s, 2H), 5.00 (s, 2H),4.83 (br s, 2H), 4.54 (br s, 1H), 4.07 (q, J=7.1 Hz, 2H), 3.59 (q, J=7.0Hz, 2H), 1.79-0.96 (m, 10H), 1.24 (t, J=7.0 Hz, 3H), 1.21 (t, J=7.2 Hz,3H); MS (APCI) m/z 426 (M+H)⁺; Anal. Calcd for C₂₃H₃₁N₅O₃.0.25 H₂O: C,64.24; H, 7.38; N, 16.29. Found: C, 63.99; H, 7.41; N, 16.31.

Example 1301-{[4-Amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclobutanol

Part A

Under a nitrogen atmosphere a mixture of1-[(3-aminoquinolin-4-ylamino)methyl]cyclobutanol (6.65 g, 27.3 mmol,Example 8 Parts A through D), triethylamine (3.81 mL, 27.3 mmol), anddichloromethane (200 mL) was cooled in an ice bath. 3-Methoxypropionylchloride (3.35 g, 27.3 mmol) was added dropwise. The reaction mixturewas kept cool for 2 hours and then allowed to warm to ambienttemperature overnight. More acid chloride (0.25 eq) was added and thereaction mixture was stirred for 4 hours. The reaction mixture waswashed with water. The organic layer was concentrated under reducedpressure to provide crude amide intermediate as an orange foamy solid.This material was purified by column chromatography (silica gel elutingwith 80/20 dichloromethane/methanol) to provide 5.2 g of a white foamysolid. This material was dissolved in ethanol (100 mL) and triethylamine(10 mL). The solution was refluxed for 4 days and then concentratedunder reduced pressure. The residue was purified by columnchromatography (silica gel eluting with 85/15 ethyl acetate/methanol) toprovide 3.51 g of1-{[2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclobutanolas a white foamy solid.

Part B

The material from Part A was oxidized and then aminated according to thegeneral methods of Part F of Example 9. The crude product was purifiedby column chromatography (silica gel eluting with a gradient of 10-20%methanol in dichloromethane) to provide a light tan oil. This materialwas triturated with acetonitrile. The resulting solid was isolated byfiltration and dried in a vacuum oven at 80° C. to provide 1.85 g of1-{[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclobutanolas light tan crystals, mp 169-171° C. ¹H NMR (300 MHz, DMSO-d₆) δ 8.31(m, 1H), 7.60 (dd, J=8.3, 1.3 Hz, 1H), 7.38 (ddd, J=8.2, 7.1, 1.2 Hz,1H), 7.21 (ddd, J=8.3, 6.9, 1.3 Hz, 1H), 6.44 (br s, 2H), 5.53 (s, 1H),4.70 (br s, 2H), 3.81 (t, J=6.9 Hz, 2H), 3.29 (t, J=6.9 Hz, 2H), 3.28(s, 3H), 2.08 (m, 2H), 1.90 (m, 2H), 1.73 (m, 2H); MS (APCI) m/z 327(M+H)⁺; Anal. Calcd for C₁₈H₂₂N₄O₂: C, 66.24; H, 6.79; N, 17.16. Found:C, 66.05; H, 6.64; N, 17.28.

Example 1311-{[4-Amino-2-(2-hydroxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclobutanol

Under a nitrogen atmosphere a mixture of1-{[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclobutanol(1.43 g, 4.38 mmol) and dichloromethane (30 mL) was cooled in an icebath. Boron tribromide (11.0 mL of 1M in dichloromethane) was addeddropwise. The reaction mixture was allowed to warm to ambienttemperature after 1 hour and then stirred for 6 hours. The reactionmixture was combined with a smaller scale run. Methanol (20 mL) wasadded and the reaction mixture was stirred for 20 minutes. Hydrochloricacid (20 mL of 6N) was added. The reaction mixture was heated at 40° C.for 2 hours and then allowed to stir at ambient temperature overnight.The reaction mixture was made basic (pH 13) with 50% sodium hydroxideand then extracted with dichloromethane (5×100 mL). The combinedorganics were concentrated under reduced pressure. The residue waspurified by column chromatography (silica gel eluting with a gradient of10-30% methanol in dichloromethane) to provide 1.2 g of a white frothysolid. This material was triturated with ethyl acetate to provide awhite solid which was recrystallized from water (100 mL) to provide 0.83g of1-{[4-amino-2-(2-hydroxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclobutanolas white needles, mp 132-137° C. ¹H NMR (300 MHz, DMSO-d₆) δ 8.31 (m,1H), 7.59 (dd, J=8.3, 1.2 Hz, 1H), 7.38 (ddd, J=8.2, 7.1, 1.1 Hz, 1H),7.20 (ddd, J=8.3, 6.9, 1.2 Hz, 1H), 6.47 (br s, 2H), 5.52 (s, 1H), 4.85(t, J=5.6 Hz, 1H), 4.71 (br s, 2H), 3.86 (m, 2H), 3.19 (t, J=6.6 Hz,2H), 2.09 (m, 2H), 1.90 (m, 2H), 1.72 (m, 2H); MS (APCI) m/z 313 (M+H)⁺;Anal. Calcd for C₁₇H₂₀N₄O₂.0.50 H₂O: C, 63.53; H, 6.59; N, 17.43. Found:C, 63.76; H, 6.19; N, 17.52.

Example 1321-[4-Amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]cyclobutanol

1-[4-Chloro-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]cyclobutanol(2.95 g, 9.34 mmol, prepared according to the general methods of Example8 using 2,4-dichloro-3-nitroquinoline in lieu of4-chloro-3-nitroquinoline in Part C and propionyl chloride in lieu ofethoxyacetyl chloride in Part E), ammonium chloride (0.50 g, 9.34 mmol),and ammonia in methanol (90 mL of 7.0 N) were combined in a bombreactor. The reactor was sealed and heated at 150° for 48 hours. Thereaction mixture was filtered and concentrated under reduced pressure toprovide a tan solid. This material was recrystallized fromacetonitrile/ethanol and dried under vacuum at 80° C. to provide 1.14 gof 1-[4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]cyclobutanolas light tan crystals, mp 226-228° C. ¹H NMR (300 MHz, DMSO-d₆) δ 8.30(m, 1H), 7.59 (dd, J=8.3, 1.2 Hz, 1H), 7.37 (ddd, J=8.3, 7.0, 1.2 Hz,1H), 7.20 (ddd, J=8.3, 6.9, 1.2 Hz, 1H), 6.40 (br s, 2H), 5.51 (s, 1H),4.65 (br s, 2H), 3.03 (q, J=7.4 Hz, 2H), 2.08 (m, 2H), 1.90 (m, 2H),1.71 (m, 2H), 1.35 (t, J=7.4 Hz, 3H); MS (APCI) m/z 297 (M+H)⁺; Anal.Calcd for C₁₇H₂₀N₄O: C, 68.90; H, 6.80; N, 18.90. Found: C, 68.71; H,7.16; N, 18.94.

Example 1331-[4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]cyclobutanol

1-[4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]cyclobutanolwas prepared according to the method of Example 132 using valerylchloride in lieu of propionyl chloride. The crude product waspartitioned between 5% sodium carbonate (100 mL) and dichloromethane(200 mL). The organic was concentrated under reduced pressure to providea tan solid, which was purified by column chromatography (silica geleluting with 85/15 dichloromethane/methanol) to provide a white solid.This solid was recrystallized from isopropanol then dissolved inmethanol. The solution was concentrated under reduced pressure toprovide a white solid, which was dried under vacuum at 80° C. to providepure product as a white solid, mp 186-188° C. ¹H NMR (300 MHz, DMSO-d₆)δ 8.30 (m, 1H), 7.59 (dd, J=8.4, 1.2 Hz, 1H), 7.37 (ddd, J=8.3, 7.0, 1.2Hz, 1H), 7.20 (ddd, J=8.3, 6.9, 1.2 Hz, 1H), 6.40 (br s, 2H), 5.50 (s,1H), 4.65 (br s, 2H), 3.00 (m, 2H), 2.08 (m, 2H), 1.98-1.58 (m, 6H),1.43 (sextet, J=7.4 Hz, 2H), 0.94 (t, J=7.3 Hz, 3H); MS (APCI) m/z 325(M+H)⁺; Anal. Calcd for C₁₉H₂₄N₄O: C, 70.34; H, 7.46; N, 17.27. Found:C, 70.26; H, 7.62; N, 17.27.

Example 1344-[(4-Amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]-4-hydroxy-N-phenylpiperidine-1-carboxamide

Part A

Under a nitrogen atmosphere a mixture of trifluoroacetic acid (40 mL)and dichloromethane (200 mL) was chilled in an ice bath. A solution oftert-butyl4-[(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]-4-hydroxypiperidine-1-carboxylate(20 g, Example 4 Parts A through E) in dichloromethane (200 mL) wasslowly added. The reaction mixture was allowed to warm to ambienttemperature, stirred for 6 hours, and then concentrated under reducedpressure to provide a dark amber oil. The oil was dissolved in water(200 mL), the pH was adjusted to 13 with 50% sodium hydroxide, and themixture was extracted with dichloromethane. The combined extracts weredried over magnesium sulfate, filtered, and concentrated under reducedpressure to provide 15.2 g of4-[(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]piperidin-4-olas a tan frothy solid.

Part B

Under a nitrogen atmosphere phenyl isocyanate (1.00 mL, 9.25 mmol) wasadded dropwise to a chilled mixture of4-[(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]piperidin-4-ol(3.00 g, 8.81 mmol) and dichloromethane (90 mL). The reaction mixturewas allowed to warm to ambient temperature. After 2 hours the reactionmixture was concentrated under reduced pressure to provide an orangeoil. This material was triturated with diethyl ether to provide 4.1 g of4-[(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]-4-hydroxy-N-phenylpiperidine-1-carboxamideas a light orange solid.

Part C

The material from Part B was oxidized and aminated according to thegeneral methods of Part F of Example 10. The crude product was purifiedby column chromatography (eluting with a gradient of 10-30% methanol indichloromethane) to provide 1.5 g of a white frothy solid. This materialwas recrystallized from acetonitrile (12 mL) and dried under vacuum at80° C. to provide4-[(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]-4-hydroxy-N-phenylpiperidine-1-carboxamideas white crystals, mp 184-186° C. ¹H NMR (300 MHz, DMSO-d₆) δ 8.40 (s,1H), 8.34 (m, 1H), 7.59 (dd, J=8.4, 1.2 Hz, 1H), 7.45-7.36 (m, 3H),7.24-7.16 (m, 3H), 6.90 (ddd, J=8.4, 7.2, 1.1 Hz, 1H), 6.56 (br s, 2H),5.29-4.34 (m, 4H), 5.02 (s, 1H), 3.90 (m, 2H), 3.53 (q, J=7.0 Hz, 2H),2.95 (m, 2H), 1.75 (m, 2H), 1.39 (br s, 2H), 1.14 (t, J=7.0 Hz, 3H); MS(APCI) m/z 475 (M+H)⁺; Anal. Calcd for C₂₆H₃₀N₆O₃.0.25 H₂O: C, 65.19; H,6.42; N, 17.54. Found: C, 64.80; H, 6.38; N, 17.45.

Example 1354-[4-Amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]-1-(cyclopropylcarbonyl)piperidin-4-ol

Part A

Under a nitrogen atmosphere cyclopropanecarbonyl chloride (0.84 mL, 9.25mmol) was added dropwise to a chilled mixture of4-[(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]piperidin-4-ol(3.00 g, 8.81 mmol), triethylamine (1.47 mL, 10.6 mmol) anddichloromethane (90 mL). The reaction mixture was allowed to warm toambient temperature. After 2 hours the reaction mixture was washed withwater. The organic layer was concentrated under reduced pressure. Theresidue was purified by column chromatography (silica gel eluting with90/10 dichloromethane/methanol) to provide 3.16 g of4-[2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]-1-(cyclopropylcarbonyl)piperidin-4-olas a light orange frothy solid.

Part B

The material from Part A was oxidized and aminated according to thegeneral methods of Part F of Example 10. The crude product was purifiedby column chromatography (silica gel eluting with a gradient of 15-20%methanol in dichloromethane) to provide 1.9 g of a white frothy solid.This material product was purified by column chromatography (silica geleluting with 80/20 ethyl acetate/methanol) to provide a clear oil. Thismaterial was dissolved in hot water (100 mL) and the solution wasallowed to cool to ambient temperature. A precipitate was isolated byfiltration and dried under vacuum at 60° C. to provide 1.39 g of4-[4-amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]-1-(cyclopropylcarbonyl)piperidin-4-olas white crystals, mp 128-131° C. ¹H NMR (300 MHz, DMSO-d₆) δ 8.33 (m,1H), 7.59 (dd, J=8.3, 1.2 Hz, 1H), 7.40 (m, 1H), 7.21 (ddd, J=8.3, 6.9,1.3 Hz, 1H), 6.56 (br s, 2H), 5.40-4.40 (m, 4H), 5.07 (s, 1H), 4.10 (m,2H), 3.53 (q, J=7.0 Hz, 2H), 2.97 (m, 2H), 2.00-1.20 (m, 5H), 1.13 (t,J=7.0 Hz, 3H), 0.79-0.56 (m, 4H); MS (APCI) m/z 424 (M+H)⁺; Anal. Calcdfor C₂₃H₂₉N₅O₃.1.00 H₂O: C, 62.57; H, 7.08; N, 15.86. Found: C, 62.78;H, 7.04; N, 15.92.

Example 1364-[4-Amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]-4-hydroxy-N,N-dimethylpiperidine-1-carboxamide

4-[4-Amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]-4-hydroxy-N,N-dimethylpiperidine-1-carboxamidewas prepared according to the general methods of Example 135 usingdimethylcarbamoyl chloride in lieu of cyclopropanecarbonyl chloride inPart A. The crude product was purified by column chromatography (elutingwith a gradient of 15-20% methanol in dichloromethane) to provide awhite solid. This material was recrystallized from acetonitrile toprovide 1.3 g of a tan solid. The solid was dissolved in methanol andconcentrated hydrochloric acid was added. The mixture was stirred for 30minutes and then concentrated under reduced pressure to provide thehydrochloride salt as an oil. The oil was dissolved in water (100 mL)and then sodium carbonate (5 g) was added. A precipitate was isolated byfiltration and dried in a vacuum oven at 50° C. to provide 0.92 g ofpure product as a white powder, mp 115-125° C. ¹H NMR (300 MHz, DMSO-d₆)δ 8.32 (m, 1H), 7.59 (dd, J=8.3, 1.2 Hz, 1H), 7.40 (m, 1H), 7.20 (ddd,J=8.2, 6.9, 1.2 Hz, 1H), 6.57 (br s, 2H), 5.50-4.20 (m, 4H), 4.95 (s,1H), 3.52 (q, J=7.0 Hz, 2H), 3.28 (m, 2H), 2.89 (m, 2H), 2.68 (s, 6H),1.75 (m, 2H), 1.34 (m, 2H), 1.13 (t, J=6.9 Hz, 3H); MS (APCI) m/z 427(M+H)⁺; Anal. Calcd for C₂₂H₃₀N₆O₃: C, 61.95; H, 7.09; N, 19.70. Found:C, 61.71; H, 7.18; N, 19.50.

Example 1374-[4-Amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]-1-(propylsulfonyl)piperidin-4-ol

Part A

Under a nitrogen atmosphere, 1-propanesulfonyl chloride (1.04 mL, 9.25mmol) was added dropwise to a chilled mixture of4-[(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]piperidin-4-ol(3.00 g, 8.81 mmol), dimethylaminopyridine (3.00 g), pyridine (10 mL),and dichloromethane (60 mL). The reaction mixture was allowed to warm toambient temperature. After 2 hours the reaction mixture was concentratedunder reduced pressure. The residue was partitioned between water (100mL) and dichloromethane (100 mL). The aqueous layer was extracted withdichloromethane (2×100 mL). The combined organics were concentratedunder reduced pressure to provide an orange oil. The oil was purified bycolumn chromatography (silica gel eluting with 95/5dichloromethane/methanol) to provide 3.68 g of4-[(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]-1-(propylsulfonyl)piperidin-4-oas a light orange frothy solid.

Part B

The material from Part A was oxidized and aminated according to thegeneral methods of Part F of Example 10. The crude product was purifiedby column chromatography (silica gel eluting with 90/10dichloromethane/methanol) to provide a white solid. This material wasrecrystallized for ethyl acetate to provide 1.8 g of a white crystallinesolid. This solid was purified by column chromatography (silica geleluting with 80/20 ethyl acetate/methanol) to provide a clear oil. Theoil was triturated with hot water. The resulting solid was isolated byfiltration and dried in a vacuum oven at 80° C. to provide4-[4-amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]-1-(propylsulfonyl)piperidin-4-olas white crystals, mp 211-213° C. ¹H NMR (300 MHz, DMSO-d₆) δ 8.34 (m,1H), 7.60 (dd, J=8.3, 1.1 Hz, 1H), 7.41 (m, 1H), 7.23 (m, 1H), 6.57 (brs, 2H), 5.50-4.20 (m, 4H), 5.05 (s, 1H), 3.53 (q, J=6.9 Hz, 2H), 3.35(m, 2H), 3.05-2.80 (m, 4H), 1.95-1.20 (m, 6H), 1.14 (t, J=7.0 Hz, 3H),0.96 (t, J=7.3 Hz, 3H); MS (APCI) m/z 462 (M+H)⁺; Anal. Calcd forC₂₂H₃₁N₅O₄S: C, 57.25; H, 6.77; N, 15.17. Found: C, 57.10; H, 6.97; N,15.24.

Example 1384-[4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]-1-(methylsulfonyl)piperidin-4-ol

Part A

The BOC protecting group was removed from tert-butyl4-[(4-chloro-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]-4-hydroxypiperidine-1-carboxylate(3.55 g, prepared according to the general methods of Example 4 using2,4-dichloro-3-nitroquinoline in lieu of 4-chloro-3-nitroquinoline inPart C and valeryl chloride in lieu of ethoxyacetyl chloride in Part E)using the method of Part A of Example 134 to provide 2.60 g of4-[4-chloro-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]piperidin-4-olas a tan solid.

Part B

Under a nitrogen atmosphere, methanesulfonyl chloride (0.53 mL, 7.18mmol) was added dropwise to a chilled mixture of the material from PartA (2.55 g, 6.84 mmol), dimethylaminopyridine (1.27 g), pyridine (10 mL),and dichloromethane (75 mL). The reaction was maintained at 0° C. for 2hours and then allowed to warm to ambient temperature. After 16 hoursthe reaction mixture was washed with water (100 mL). The aqueous layerwas extracted with dichloromethane (2×100 mL). The combined organicswere concentrated under reduced pressure. The residue was purified bycolumn chromatography (silica gel eluting with 95/5dichloromethane/methanol) to provide 2.60 g of4-[4-chloro-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]-1-(methylsulfonyl)piperidin-4-olas a white foamy solid.

Part C

A portion (2.35 g, 5.21 mmol) of the material from Part B, ammoniumchloride (0.28 g, 5.21 mmol), and ammonia in methanol (50 mL of 7.0 N)were combined in a bomb reactor. The reactor was sealed and heated at150° for 48 hours. The reaction mixture was filtered and thenconcentrated under reduced pressure. The residue was partitioned between5% sodium carbonate and dichloromethane. The aqueous layer was extractedwith dichloromethane (×2). The combined organics were concentrated underreduced pressure to provide an amber oil. The oil was purified by columnchromatography (silica gel eluting with 90/10 dichloromethane/methanol)to provide a clear oil. This material was triturated with acetonitrileto provide a solid. The solid was suspended in water (100 mL),concentrated hydrochloric acid (5 mL) was added, and the mixture wasstirred for 2 hours. Sodium carbonate (10 g) was added and the mixturewas heated at 45° C. for 1 hour. The mixture was allowed to cool toambient temperature. A solid was isolated by filtration and dried in avacuum oven at 80° C. to provide 1.43 g of4-[4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]-1-(methylsulfonyl)piperidin-4-olas a white solid, mp 240-242° C. ¹H NMR (300 MHz, DMSO-d₆) δ 8.32 (m,1H), 7.58 (dd, J=8.3, 1.2 Hz, 1H), 7.37 (m, 1H), 7.21 (ddd, J=8.3, 6.9,1.3 Hz, 1H), 6.40 (br s, 2H), 5.00-4.20 (m, 2H), 4.94 (s, 1H), 3.34 (m,2H), 3.32 (br t, J=7.7 Hz, 2H), 2.85 (m, 2H), 2.81 (s, 3H), 2.00-1.10(m, 6H), 1.43 (sextet, J=7.4 Hz, 2H), 0.95 (t, J=7.3 Hz, 3H); MS (APCI)m/z 432 (M+H)⁺; Anal. Calcd for C₂₁H₂₉N₅O₃S.0.25 H₂O: C, 57.84; H, 6.82;N, 16.06. Found: C, 57.71; H, 7.00; N, 16.00.

Example 1394-[4-Amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]-1-(methylsulfonyl)piperidin-4-ol

4-[4-Amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]-1-(methylsulfonyl)piperidin-4-olwas prepared according to the general methods of Example 138 usingbutyry chloride in lieu of valeryl chloride. The crude product waspurified by column chromatography (silica gel eluting with a gradient of10-20% methanol in dichloromethane) to provide a white solid. Thismaterial was recrystallized from acetonitrile and then from methanol.The resulting solid was dissolved in water (100 mL), concentratedhydrochloric acid (10 mL) was added, and the mixture was stirred for 1hour. Sodium carbonate (10 g) was added and the mixture was heated at40° C. for 1 hour. A solid was isolated by filtration and dried in avacuum oven at 80° C. to provide pure product as a white solid, mp>250°C. ¹H NMR (300 MHz, DMSO-d₆, 354 K) δ 8.29 (m, 1H), 7.60 (dd, J=8.3, 1.2Hz, 1H), 7.36 (ddd, J=8.2, 7.0, 1.2 Hz, 1H), 7.20 (ddd, J=8.2, 7.0, 1.2Hz, 1H), 6.06 (br s, 2H), 4.72 (br s, 1H), 4.60 (br s, 2H), 3.36 (m,2H), 3.06-2.84 (m, 4H), 2.78 (s, 3H), 1.94-1.72 (m, 4H), 1.53 (m, 2H),1.02 (t, J=7.3 Hz, 3H); MS (APCI) m/z 418 (M+H)⁺; Anal. Calcd forC₂₀H₂₇N₅O₃S.0.50 H₂O: C, 56.32; H, 6.62; N, 16.42. Found: C, 56.41; H,6.39; N, 16.49.

Example 1404-[4-Amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]-1-(methylsulfonyl)piperidin-4-ol

4-[4-Amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]-1-(methylsulfonyl)piperidin-4-olwas prepared according to the general methods of Example 138 usingpropionyl chloride in lieu of valeryl chloride. The crude product wassuspended in water, isolated by filtration, and then dried to provide awhite solid. This material was recrystallized twice from acetonitrile toprovide 0.95 g of pure product as white needles, mp 260-262° C. ¹H NMR(300 MHz, DMSO-d₆, 354 K) δ 8.29 (dd, J=8.3, 1.0 Hz, 1H), 7.60 (dd,J=8.3, 1.1 Hz, 1H), 7.36 (ddd, J=8.3, 7.0, 1.3 Hz, 1H), 7.20 (ddd,J=8.3, 6.9, 1.4 Hz, 1H), 6.04 (br s, 2H), 4.73 (br s, 1H), 4.60 (s, 2H),3.37 (m, 2H), 3.03 (q, J=7.5 Hz, 2H), 2.92 (m, 2H), 2.78 (s, 3H), 1.80(app. td, J=12.8, 4.7 Hz, 2H), 1.53 (m, 2H), 1.37 (t, J=7.5 Hz, 3H); MS(APCI) m/z 404 (M+H)⁺; Anal. Calcd for C₁₉H₂₅N₅O₃S: C, 56.56; H, 6.25;N, 17.36. Found: C, 56.38; H, 6.45; N, 17.53.

Example 1414-[4-Amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]-1-(methylsulfonyl)piperidin-4-ol

4-[4-Amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]-1-(methylsulfonyl)piperidin-4-olwas prepared according to the general methods of Example 138 usingacetyl chloride in lieu of valeryl chloride. The crude product wasisolated by filtration, washed with methanol, and then dissolved in hotDMF. The solution was allowed to cool to ambient temperature. A solidwas isolated by filtration, washed with DMF, and then dissolved in hotwater. A precipitate was isolated by filtration and dried under vacuumat 80° C. to provide pure product as a white solid, mp 294-296° C. ¹HNMR (300 MHz, DMSO-d₆) δ 8.33 (m, 1H), 7.58 (dd, J=8.3, 1.2 Hz, 1H),7.37 (m, 1H), 7.20 (m, 1H), 6.44 (br s, 2H), 4.97 (s, 1H), 4.60 (br s,2H), 3.34 (m, 2H), 2.87 (m, 2H), 2.82 (s, 3H), 2.66 (s, 3H), 1.85 (m,2H), 1.54 (m, 2H); MS (APCI) m/z 390 (M+H)⁺; Anal. Calcd forC₁₈H₂₃N₅O₃S: C, 55.51; H, 5.95; N, 17.98. Found: C, 55.29; H, 6.18; N,17.95.

Example 1424-[4-Amino-1H-imidazo[4,5-c]quinolin-1-yl)methyl]-1-(methylsulfonyl)piperidin-4-ol

Part A

Under a nitrogen atmosphere, tert-butyl 4{[(3-amino-2-chloroquinolin-4-yl)amino]methyl}-4-hydroxypiperidine-1-carboxylate(0.25 g, 0.61 mmol, prepared according to the general methods of Example4 Parts A through D using 2,4-dichloro-3-nitroquinoline in lieu of4-chloro-3-nitroquinoline in Part C), toluene (5 mL), pyridinehydrochloride (0.02 g), and triethylorthoformate (0.11 mL, 0.65 mmol)was heated at reflux for 2 hours. More triethylorthoformate (0.5 eq) wasadded and the reaction mixture was heated for an additional hour. Thereaction was rerun in the same manner using 5.25 g of tert-butyl 4{[(3-amino-2-chloroquinolin-4-yl)amino]methyl}-4-hydroxypiperidine-1-carboxylate.The small and larger scale reaction mixtures were combined and washedwith water (50 mL). The aqueous layer was extracted with dichloromethane(2×100 mL). The organic layers were combined and concentrated underreduced pressure. The residue was purified by column chromatography(silica gel eluting with a gradient of 0-10% methanol in ethyl acetate)to provide 4.08 g of tert-butyl4-[(4-chloro-1H-imidazo[4,5-c]quinolin-1-yl)methyl]-4-hydroxypiperidine-1-carboxylateas a tan frothy solid.

Part B

The material from part A was converted to4-[4-amino-1H-imidazo[4,5-c]quinolin-1-yl)methyl]-1-(methylsulfonyl)piperidin-4-olaccording to the general methods of Example 138. The crude product wasisolated by filtration, washed with methanol, recrystallized frommethanol/water, and then dried in a vacuum oven at 80° C. to provide0.84 g of pure product as white needles, mp>250° C. ¹H NMR (300 MHz,DMSO-d₆, 354 K) δ 8.33 (m, 1H), 8.04 (s, 1H), 7.61 (m, 1H), 7.40 (ddd,J=8.3, 7.0, 1.3 Hz, 1H), 7.22 (ddd, J=8.3, 6.9, 1.3 Hz, 1H), 6.18 (br s,2H), 4.81 (br s, 1H), 4.61 (s, 2H), 3.40 (m, 2H), 2.99 (m, 2H), 2.80 (s,3H), 1.78 (m, 2H), 1.53 (m, 2H); MS (APCI) m/z 376 (M+H)⁺; Anal. Calcdfor C₁₇H₂₁N₅O₃S: C, 54.38; H, 5.64; N, 18.65. Found: C, 54.18; H, 5.68;N, 18.64.

Example 1431-[(4-Aminotetrahydro-2H-pyran-4-yl)methyl]-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine

Part A

Tert-Butyl{4-[(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]tetrahydropyran-4-yl}carbamate(1.70 g, prepared according to the general methods of Parts A through Fof Example 54 using tetrahydro-4H-pyran-4-one in lieu of cyclohexanonein Part A) was oxidized and aminated according to the general method ofPart F of Example 10 to provide 1.13 g of tert-Butyl{4-[(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]tetrahydropyran-4-yl}carbamateas a light brown solid.

Part B

The material from Part A was combined with hydrochloric acid (20 mL of2.8 M in ethanol) and heated at reflux for six hours. The reactionmixture was concentrated under reduced pressure and the residue waspartitioned between 10% sodium hydroxide (100 mL) and dichloromethane(100 mL). The aqueous layer was extracted with dichloromethane (2×100mL). The pH of the aqueous was adjusted to pH 11 with hydrochloric acidand sodium carbonate and then extracted with dichloromethane (3×100 mL).The combined organics were dried over sodium sulfate, filtered, and thenconcentrated under reduced pressure to provide 0.95 g of an amber oil.This material was purified by column chromatography (silica gel elutingwith 90/10 dichloromethane/methanol) to provide 0.45 g of a white solid.This material was dissolved in methanol and then dried in a vacuum ovenat 40° C. to provide1-[(4-aminotetrahydro-2H-pyran-4-yl)methyl]-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amineas a white frothy solid, mp 53-63° C. ¹H NMR (300 MHz, CDCl₃) δ 8.19(dd, J=8.3, 1.0 Hz, 1H), 7.81 (dd, J=8.4, 0.9 Hz, 1H), 7.51 (ddd, J=8.4,7.0, 1.4 Hz, 1H), 7.30 (ddd, J=8.3, 7.0, 1.3 Hz, 1H), 5.50 (br s, 2H),4.97 (br s, 2H), 4.69 (br s, 2H), 3.82-3.63 (m, 4H), 3.59 (q, J=7.0 Hz,2H), 2.10-1.27 (m, 6H), 1.24 (t, J=7.0 Hz, 3H); MS (ESI) m/z 356 (M+H)⁺;Anal. Calcd for C₁₉H₂₅N₅O₂.0.50 H₂O: C, 62.62; H, 7.19; N, 19.22. Found:C, 62.61; H, 7.20; N, 19.20.

Example 144N-{[4-(4-Amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]tetrahydropyran-4-yl}methanesulfonamide

Part A

Under a nitrogen atmosphere, a mixture of tert-Butyl{4-[(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]tetrahydropyran-4-yl}carbamate(3.0 g, prepared according to the general methods of Parts A through Fof Example 54 using tetrahydro-4H-pyran-4-one in lieu of cyclohexanonein Part A), hydrochloric acid (12.2 mL of 2.8 M in ethanol), and ethanol(18 mL) was heated at reflux for 4 hours. The reaction mixture wasallowed to cool to ambient temperature and was then concentrated underreduced pressure. The residue was combined with isopropanol (100 mL). Asolid was isolated by filtration to provide 2.56 g of4-[(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]tetrahydropyran-4-amineas a tan solid.

Part B

Under a nitrogen atmosphere, methanesulfonyl chloride (0.068 mL, 0.88mmol) was added dropwise to a chilled mixture of the material from PartA (0.25 g, 0.73 mmol), dimethylaminopyridine (0.25 g), pyridine (2 mL),and dichloromethane (2.5 mL). The reaction was maintained at 0° C. for 1hour, allowed to warm to ambient temperature, and then stirred for 16hours. The reaction was repeated on a larger scale using the remainderof the material from Part A. The reaction mixtures were combined andconcentrated under reduced pressure. The residue was partitioned betweenwater (100 mL) and dichloromethane (100 mL). The aqueous layer wasextracted with dichloromethane (100 mL). The combined organics weredried over magnesium sulfate, filtered, and then concentrated underreduced pressure. The residue was purified by column chromatography(silica gel eluting with 80/20 ethyl acetate/methanol) to provide 1.64 gofN-{[4-(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]tetrahydropyran-4-yl}methanesulfonamideas a light yellow solid.

Part C

The material from Part B was oxidized and aminated according to thegeneral method of Part F of Example 10. The crude product waspartitioned between water (100 mL) and dichloromethane (100 mL). Theaqueous layer was extracted with dichloromethane (2×100 mL). The pH ofthe aqueous was adjusted to pH 11 with hydrochloric acid and sodiumcarbonate and then extracted with dichloromethane (2×100 mL). Thecombined organics were dried over magnesium sulfate, filtered, and thenconcentrated under reduced pressure to provide a clear oil. The oil waspurified by column chromatography (silica gel eluting with 90/10dichloromethane/methanol) to provide 0.90 g of a clear oil. Thismaterial was dissolved in methanol and then dried in a vacuum oven at50° C. to provide 0.86 g ofN-{[4-(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]tetrahydropyran-4-yl}methanesulfonamideas a white frothy solid, mp 97-110° C. ¹H NMR (300 MHz, CDCl₃) δ 8.20(dd, J=8.3, 0.9 Hz, 1H), 7.80 (dd, J=8.4, 1.1 Hz, 1H), 7.51 (ddd, J=8.3,7.0, 1.3 Hz, 1H), 7.29 (ddd, J=8.3, 6.9, 1.3 Hz, 1H), 6.02 (br s, 1H),5.66 (br s, 2H), 5.25 (br s, 2H), 4.90 (br s, 2H), 3.78-3.58 (m, 4H),3.68 (q, J=7.0 Hz, 2H), 3.20 (s, 3H), 2.70-1.30 (m, 4H), 1.23 (t, J=7.0Hz, 3H); MS (APCI) m/z 434 (M+H)⁺; Anal. Calcd for C₂₀H₂₇N₅O₄S.0.75 H₂O:C, 53.74; H, 6.43; N, 15.67. Found: C, 53.87; H, 6.34; N, 15.70.

Example 1451-[(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]cyclohexanol

1-[(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]cyclohexanolwas prepared according to the general methods of Example 1 using valerylchloride in lieu of ethoxyacetyl chloride in Part B. The crude productwas recrystallized from acetonitrile to provide pure product as a brownsolid, mp 218-220° C. ¹H NMR (300 MHz, DMSO-d₆) δ 8.30 (d, J=8.1 Hz,1H), 7.57 (d, J=6.9 Hz, 1H), 7.36 (t, J=6.9 Hz, 1H), 7.19 (t, J=8.1 Hz,1H), 6.37, (br s, 2H), 4.53 (s, 1H), 4.51 (br s, 1H), 3.01 (t, J=8.1 Hz,2H), 1.79 (pent, J=7.5 Hz, 2H), 1.46 (hex, J=7.5 Hz, 2H), 1.43 (m, 10H),1.10 (br s, 1H), 0.94 (t, J=6.9 Hz, 3H); MS (APCI) m/z 353 (M+H)⁺; Anal.calcd for C₂₁H₂₈N₄O: C, 71.56; H, 8.01; N, 15.89. Found: C, 71.29; H,8.01; N, 16.02.

Example 1461-{[4-Amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexanol

1-{[4-Amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexanolwas prepared according to the general methods of Example 1 using3-methoxypropionyl chloride in lieu of ethoxyacetyl chloride in Part B.The crude product was purified by column chromatography (silica geleluting with 5% methanol in chloroform), recrystallized fromacetonitrile/water, and then dried in a vacuum oven at 105° C. toprovide hydrated product as a light brown solid, mp 189-191° C. ¹H NMR(300 MHz, DMSO-d₆) δ 8.30 (d, J=8.1 Hz, 1H), 7.57 (d, J=8.1 Hz, 1H),7.37 (t, J=8.1 Hz, 1H), 7.19 (t, J=8.1 Hz, 1H), 6.39, (br s, 2H), 4.56(s, 1H), 4.54 (br s, 1H), 3.81 (t, J=6.9 Hz, 2H), 3.30 (m, 2H), 3.28 (s,3H), 1.47 (m, 10H), 1.10 (br s, 1H); MS (APCI) m/z 355 (M+H)⁺; Anal.calcd for C₂₀H₂₆N₄O₂.0.29 H₂O: C, 66.79; H, 7.45; N, 15.58. Found: C,66.74; H, 7.54; N, 15.81.

Example 1471-[(4-Amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]cyclohexanol

1-[(4-Amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]cyclohexanolwas prepared according to the general methods of Example 1 using butyrylchloride in lieu of ethoxyacetyl chloride in Part B. The crude productwas purified twice by HPFC eluting the first time with a gradient of2-40% CMA in chloroform and the second time with a gradient of 8-25% CMAin chloroform to provide pure product as an off-white solid, mp 250-252°C. ¹H NMR (300 MHz, DMSO-d₆) δ 8.30 (d, J=7.5 Hz, 1H), 7.57 (d, J=7.5Hz, 1H), 7.36 (t, J=7.5 Hz, 1H), 7.19 (t, J=7.5 Hz, 1H), 6.36, (br s,2H), 4.52 (s, 1H), 4.49 (br s, 1H), 2.99 (t, J=7.5 Hz, 2H), 1.83 (hex,J=7.5 Hz, 2H), 1.46 (m, 10H), 1.10 (br s, 1H), 1.00 (t, J=7.5 Hz, 3H);MS (APCI) m/z 339 (M+H)⁺; Anal. calcd for C₂₀H₂₆N₄O: C, 70.98; H, 7.74;N, 16.55. Found: C, 70.73; H, 7.73; N, 16.44.

Example 1481-[(4-Amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]cyclohexanol

1-[(4-Amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]cyclohexanolwas prepared according to the general methods of Example 1 usingpropionyl chloride in lieu of ethoxyacetyl chloride in Part B. The crudeproduct was recrystallized from acetonitrile/water to provide pureproduct as a brown solid, mp 217-218° C. ¹H NMR (300 MHz, DMSO-d₆) δ8.31 (d, J=7.5 Hz, 1H), 7.57 (d, J=7.5 Hz, 1H), 7.36 (t, J=7.5 Hz, 1H),7.19 (t, J=7.5 Hz, 1H), 6.36, (br s, 2H), 4.53 (s, 1H), 4.49 (br s, 1H),3.04 (q, J=7.5 Hz, 2H), 1.46 (m, 10H), 1.35 (t, J=7.5 Hz, 3H), 1.10 (brs, 1H); MS (APCI) m/z 325 (M+H)⁺; Anal. calcd for C₁₉H₂₄N₄O: C, 70.34;H, 7.46; N, 17.27. Found: C, 70.06; H, 7.34; N, 17.21.

Example 1494-[(4-Amino-1H-imidazo[4,5-c]quinolin-1-yl)methyl]tetrahydro-2H-pyran-4-ol

Part A

4-[(1H-imidazo[4,5-c]quinolin-1-yl)methyl]tetrahydro-2H-pyran-4-ol wasprepared according to the general methods of Example 11 using triethylorthoformate in lieu of triethyl orthoacetate in Part A.

Part B

4-[(1H-imidazo[4,5-c]quinolin-1-yl)methyl]tetrahydro-2H-pyran-4-ol wasoxidized and then aminated according to the general methods of Part E ofExample 2. The crude product was purified by column chromatography(silica gel eluting with 9% methanol in chloroform) and then by HPFCeluting with a gradient of 8-35% CMA in chloroform. The resultingmaterial was triturated with methanol and then dried in a vacuum oven at105° C. to provide4-[(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)methyl]tetrahydro-2H-pyran-4-olas a brown solid, mp 260-262° C. ¹H NMR (300 MHz, DMSO-d₆) δ 8.37 (d,J=8.1 Hz, 1H), 8.08 (s, 1H), 7.59 (d, J=8.1 Hz, 1H), 7.41 (t, J=8.1 Hz,1H), 7.21 (t, J=8.1 Hz, 1H), 6.51, (br s, 2H), 4.91 (s, 1H), 4.57 (br s,2H), 3.58 (m, 4H), 1.76 (dt, J=6.9 Hz, 2H), 1.31 (d, J=6.9 Hz, 2H); MS(APCI) m/z 299 (M+H)⁺; Anal. calcd for C₁₆H₁₈N₄O₂: C, 64.41; H, 6.08; N,18.78. Found: C, 64.04; H, 5.87; N, 18.83.

Example 1501-[(4-Amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]cyclopentanol

1-[(4-Amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]cyclopentanolwas prepared according to the general methods of Example 3 using acetylchloride in lieu of ethoxyacetyl chloride in Part E. The crude productwas isolated by filtration, rinsed with methanol, and then dried. Thismaterial was triturated with hot acetonitrile/water, isolated byfiltration without cooling, rinsed with water, and then dried. Theresulting material was triturated with 1N aqueous hydrochloric acid (20mL/g) for 2 hours. A solid was isolated by filtration. This solid wastriturated with a minimum amount of water and then the pH was adjustedto pH 14 using 50% aqueous sodium hydroxide. A solid was isolated byfiltration, rinsed with water, and then dried in a vacuum oven at 108°C. to provide pure product as an off-white solid, mp 306.5-307.5° C. ¹HNMR (300 MHz, DMSO-d₆) δ 8.26 (d, J=8.1 Hz, 1H), 7.57 (d, J=8.1 Hz, 1H),7.37 (d, J=7.5 Hz, 1H), 7.19 (t, J=7.5 Hz, 1H), 6.42 (br s, 2H), 4.73(s, 1H), 4.67 (s, 2H), 2.65 (s, 3H), 1.66 (m, 4H), 1.55 (m, 4H); MS(APCI) m/z 297 (M+H)⁺; Anal. calcd for C₁₇H₂₀N₄O: C, 68.89; H, 6.80; N,18.90. Found: C, 68.62; H, 6.60; N, 18.76.

Example 1511-[(4-Amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]cyclopentanol

1-[(4-Amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]cyclopentanolwas prepared according to the general methods of Example 3 usingpropionyl chloride in lieu of ethoxyacetyl chloride in Part E. The crudeproduct was recrystallized from acetonitrile/water then triturated with1N aqueous sodium hydroxide, isolated by filtration, rinsed with water,and dried under vacuum at 100° C. to provide pure product as anoff-white solid, mp 251.0-252.5° C. ¹H NMR (300 MHz, DMSO-d₆) δ 8.26 (d,J=7.5 Hz, 1H), 7.58 (d, J=8.1 Hz, 1H), 7.37 (d, J=8.1 Hz, 1H), 7.19 (t,J=8.1 Hz, 1H), 6.38 (br s, 2H), 4.71 (s, 1H), 4.68 (s, 2H), 3.03 (q,J=7.5 Hz, 2H), 1.64 (m, 4H), 1.53 (m, 4H), 1.35 (t, J=7.5 Hz, 3H); MS(APCI) m/z 311 (M+H)⁺; Anal. calcd for C₁₈H₂₂N₄O: C, 69.65; H, 7.14; N,18.05. Found: C, 69.45; H, 6.88; N, 17.94.

Example 1521-[(4-Amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]cyclopentanol

1-[(4-Amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]cyclopentanolwas prepared according to the general methods of Example 3 using butyrylchloride in lieu of ethoxyacetyl chloride in Part E. The crude productwas isolated by filtration, triturated with a minimum amount ofchloroform, isolated by filtration, and dried. The resulting materialwas triturated with 1N aqueous sodium hydroxide, isolated by filtration,and dried under vacuum at 100° C. to provide pure product as anoff-white solid, mp 209.5-210.5° C. ¹H NMR (300 MHz, DMSO-d₆) δ 8.26 (d,J=8.1 Hz, 1H), 7.58 (d, J=7.5 Hz, 1H), 7.37 (d, J=8.1 Hz, 1H), 7.19 (t,J=8.1 Hz, 1H), 6.38 (br s, 2H), 4.71 (s, 1H), 4.69 (s, 2H), 2.98 (t,J=7.5 Hz, 2H), 1.84 (hex, J=7.5 Hz, 2H), 1.63 (m, 4H), 1.53 (m, 4H),1.00 (t, J=7.5 Hz, 3H); MS (APCI) m/z 325 (M+H)⁺; Anal. calcd forC₁₉H₂₄N₄O: C, 70.34; H, 7.46; N, 17.27. Found: C, 70.27; H, 7.43; N,17.30.

Example 1531-[(4-Amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]cyclopentanol

1-[(4-Amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]cyclopentanolwas prepared according to the general methods of Example 3 using7-bromo-4-chloro-3-nitroquinoline in lieu of 4-chloro-3-nitroquinolinein Part C. The crude product was recrystallized from acetonitrile andthen from toluene to provide pure product as a brown solid, mp 128-130°C. ¹H NMR (300 MHz, DMSO-d₆) δ 8.24 (d, J=9.4 Hz, 1H), 7.71 (s, 1H),7.31 (d, J=8.7 Hz, 1H), 6.81 (br s, 2H), 4.87 (br s, 2H), 4.78 (s, 2H),4.76 (s, 1H), 3.52 (q, J=6.9 Hz, 2H), 1.66 (m, 4H), 1.51 (m, 4H), 1.13(t, J=6.9 Hz, 3H); MS (APCI) m/z 420 (M+H)⁺; Anal. calcd forC₁₉H₂₃BrN₄O₂: C, 54.42; H, 5.53; N, 13.36. Found: C, 54.18; H, 5.29; N,13.10.

Example 1541-[(4-Amino-1H-imidazo[4,5-c]quinolin-1-yl)methyl]cyclopentanol

Part A

A mixture of 1-{{(3-aminoquinolin-1-yl)amino]methyl}cyclopentanol (2.00g, 7.8 mmol, Example 3 Parts A through D), triethyl orthoformate (1.36mL, 8.2 mmol), pyridine hydrochloride (0.2 g), and toluene (20 mL) washeated at reflux for 3.5 hours. The reaction mixture was allowed to coolto ambient temperature. A solid was isolated by filtration and dried.The solid was triturated with a minimum amount of saturated aqueoussodium bicarbonate for 1 hour. The solid was filtered and then dried toprovide 1.85 g of1-[(1H-imidazo[4,5-c]quinolin-1-yl)methyl]cyclopentanol as a whitesolid.

Part B

The material from Part A was oxidized and then aminated according to thegeneral methods of Parts B and C of Example 62. The crude product wasisolated by filtration, rinsed with methanol, triturated with 1N aqueoussodium hydroxide, isolated by filtration, and then dried in a vacuumoven at 100° C. to provide1-[(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)methyl]cyclopentanol as awhite solid, mp 253.5-255.0° C. ¹H NMR (300 MHz, DMSO-d₆) δ 8.31 (d,J=8.1 Hz, 1H), 8.14 (s, 1H), 7.59 (d, J=7.5 Hz, 1H), 7.40 (t, J=7.5 Hz,1H), 7.21 (t, J=7.5 Hz, 1H), 6.50, (br s, 2H), 4.79 (s, 1H), 4.67 (s,2H), 4.69 (m, 4H), 4.55 (m, 4H); MS (APCI) m/z 283 (M+H)⁺; Anal. calcdfor C₁₆H₁₈N₄O: C, 68.06; H, 6.43; N, 19.84. Found: C, 67.89; H, 6.29; N,20.07.

Example 1551-[(4-Amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c][1,5]napthyridin-1-yl)methyl]cyclopentanol

Part A

A mixture of triethyl orthoformate (10 mL, 60.1 mmol) and2,2-dimethyl-[1,3]-dioxane-4,6-dione (40.9 g, 0.23 mol) (Meldrum's acid)was heated at 92° C. for 90 minutes and then cooled to 70° C. over onehour. 3-Amino-5-bromopyridine (40.9 g, 0.20 mol) was slowly added over10 minutes with an ethanol rinse while maintaining the reactiontemperature between 60 and 70° C. The reaction was then heated for anadditional 20 minutes and allowed to cool to room temperature. Thereaction mixture was filtered and washed with ethanol (150 mL) yieldinga tan solid. The solid was dried under vacuum for 2 hours to yield 59.14g of5-{[(5-bromopyridin-3-yl)imino]methyl}-2,2-dimethyl-1,3-dioxane-4,6-dioneas a light yellow crystalline solid, mp 200-202° C.

¹H NMR (300 MHz, CDCl₃) δ 11.26 (d, J=14.3 Hz, 1H), 8.80 (d, J=2.3 Hz,1H), 8.62 (d, J=14.3 Hz, 1H), 8.56 (d, J=1.9 Hz, 1H), 8.44-8.40 (m, 1H),1.68 (s, 6H).

Part B

5-{[(5-Bromopyridin-3-yl)imino]methyl}-2,2-dimethyl-1,3-dioxane-4,6-dione(59 g, 0.18 mol) was slowly added to DOWTHERM A heat transfer fluid(2000 mL) over a period of 5 minutes at 235-238° C. Following addition,the reaction was maintained for an additional 5 minutes and then allowedto cool to 40° C. A brown precipitate formed, which was filtered andwashed with hexanes (150 mL). The brown solid was suspended in anethanol/water mixture (90:10, 1500 mL), heated to a boil for 30 minutes,isolated by filtration, and washed with ethanol (200 mL) to yield 30.8 gof 7-bromo[1,5]naphthyridin-4-ol as a dark brown powder.

¹H NMR (300 MHz, CDCl₃) δ 11.81 (br s, 1H), 8.69 (d, J=1.9 Hz, 1H), 8.21(d, J=1.9 Hz, 1H), 7.95 (d, J=7.7 Hz, 1H), 6.22 (d, J=7.5 Hz, 1H).

Part C

A mixture of 7-bromo[1,5]naphthyridin-4-ol (33 g, 0.147 mol) and fumingnitric acid (350 mL) was heated at reflux (90° C. internal reactionvessel temperature) for 3 hours. The reaction mixture was cooled to 50°C., poured over 1 L of ice and neutralized to pH 2-3 with a solution of50% aqueous NaOH. The resulting precipitate was filtered, washed withwater, and dried over vacuum for 3 days to yield 25.1 g of7-bromo-3-nitro[1,5]naphthyridin-4-ol as a yellow crystalline solid.

¹H NMR (300 MHz, CDCl₃) δ 13.06 (br s, 1H), 9.26 (s, 1H), 8.88 (d, J=2.0Hz, 1H), 8.37 (d, J=2.0 Hz, 1H).

Part D

Phosphorous oxychloride (24 mL, 257.7 mmol) was added slowly dropwise toa 0° C. suspension of 7-bromo-3-nitro[1,5]naphthyridin-4-ol (60.00 g,222.2 mmol) in N,N-dimethylformamide (DMF; 410 mL), maintaining thetemperature below 10° C. After addition was completed, the reaction wasallowed to warm to ambient temperature over a 3 hour period. Thereaction mixture was then added to ice water (1700 mL) with stirring. Asolid precipitate formed, which was isolated by vacuum filtration andrinsed with water. The material was partitioned between chloroform (3Liters) and saturated aqueous sodium bicarbonate (300 mL). The organicphase was isolated, dried over anhydrous sodium sulfate, thenconcentrated under reduced pressure to yield 54.42 g of7-bromo-4-chloro-3-nitro[1,5]naphthyridine as short, off-white needles.

¹H NMR (300 MHz, CDCl₃) δ 9.32 (s, 1H), 9.21 (d, J=2.5 Hz, 1H), 8.71 (d,J=2.5 Hz, 1H).

Part E

1-[(4-Amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c][1,5]napthyridin-1-yl)methyl]cyclopentanolwas prepared according to the general methods of Example 3 using7-bromo-4-chloro-3-nitro[1,5]naphthyridine in lieu of4-chloro-3-nitroquinoline in Part C. The crude product was trituratedwith hot acetonitrile. The acetonitrile phase was concentrated underreduced pressure. The residue was dissolved in chloroform, washed with1% aqueous sodium bicarbonate, dried over sodium sulfate, andconcentrated under reduced pressure. The residue was purified by columnchromatography eluting with 1.5% methanol in chloroform. The resultingmaterial was triturated with hot acetonitrile. The mixture was cooled toambient temperature and a solid was isolated by filtration and dried ina vacuum oven at 110° C. to provide1-[(4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c][1,5]napthyridin-1-yl)methyl]cyclopentanolas a white solid, mp 166-167.5° C. ¹H NMR (300 MHz, DMSO-d₆) δ 8.53 (s,1H), 8.10 (s, 1H), 7.15 (br s, 2H), 5.05 (br s, 2H), 4.95 (s, 2H), 4.82(s, 1H), 3.52 (q, J=6.9 Hz, 2H), 4.64 (m, 6H), 1.39 (s, 2H), 1.14 (t,J=6.9 Hz, 3H); MS (APCI) m/z 421 (M+H)⁺; Anal. calcd for C₁₈H₂₂BrN₅O₂:C, 51.44; H, 5.28; N, 16.66. Found: C, 51.32; H, 5.24; N, 16.63.

Example 1564-[(4-Amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]-1-methylpiperidin-4-ol

Part A

Nitromethane (6.6 mL, 122.0 mmol) and sodium methoxide (0.94 mL of 25 wt% in methanol, 4.1 mmol) were added to a solution of1-methyl-4-piperidone (10 mL, 81.3 mmol) in ethanol (10 mL). After 30minutes more ethanol (15 mL) was added to facilitate stirring. Thereaction mixture was stirred at ambient temperature for 2 days and thenfiltered. The isolated solid was rinsed with ether to provide 10.39 g of1-methyl-4-nitromethylpiperidin-4-ol as a white powder. An additional1.18 g was isolated from the filtrate.

Part B

Palladium hydroxide (2.3 g of 20% on carbon) was added to a solution of1-methyl-4-nitromethylpiperidin-4-ol (11.57 g) in ethanol (120 mL). Themixture was placed under hydrogen pressure (50 psi, 3.4×10⁵ Pa) on aParr apparatus for 55 hours. The reaction mixture was filtered through alayer of CELITE filter aid and the filter cake was rinsed with methanol(100 mL). The filtrate was concentrated under reduced pressure toprovide 10.18 g of 4-aminomethyl-1-methylpiperidin-4-ol as a thick oil.

Part C

Triethylamine (10.9 mL, 78.5 mmol) was added to a suspension of2,4-dichloro-3-nitroquinoline (14.7 g, 60.4 mmol) in dichloromethane(180 mL). The mixture was cooled to 5° C. and a solution of the materialfrom Part B (66.4 mmol) in dichloromethane (70 mL) was added over aperiod of 15 minutes. The reaction mixture was stirred at 5° C. for 1hour and then at ambient temperature overnight. The reaction mixture wasconcentrated under reduced pressure. The residue was combined with water(500 mL), stirred for 1 hour, and then filtered. The isolated solid wastriturated with acetonitrile to provide 13.25 g of4-{[(2-chloro-3-nitroquinolin-4-yl)amino]methyl}-1-methylpiperidin-4-olas a bright yellow solid.

Part D

A mixture of4-{[(2-chloro-3-nitroquinolin-4-yl)amino]methyl}-1-methylpiperidin-4-ol(14.05 g), 5% platinum on carbon (1.1 g), acetonitrile (280 mL), andisopropanol (84 mL) was placed under hydrogen pressure on a Parrapparatus overnight. The reaction mixture was filtered through a layerof CELITE filter aid. The filtrate was concentrated under reducedpressure to provide crude4-{[(3-amino-2-chloroquinolin-4-yl)amino]methyl}-1-methylpiperidin-4-ol.This material was dissolved in 240 mL of acetonitrile.

Part E

Butyryl chloride (1.19 mL, 1.15 eq) was added to a 60 mL portion of thesolution from Part D. An hour later more butyryl chloride (0.1 eq) wasadded. The reaction mixture was concentrated under reduced pressure. Theresidue was triturated with diethyl ether, isolated by filtration, anddried to provide crudeN-(2-chloro-4-{[(4-hydroxy-1-methylpiperidin-4-yl)methyl]amino}quinolin-3-yl)butanamide.

Part F

A solution of 50% aqueous sodium hydroxide (2.39 g) in water (10.2 mL)was added to a solution of the material from Part E in ethanol (30 mL).The reaction mixture was refluxed for 1 hour and then concentrated underreduced pressure. The residue was partitioned between chloroform andwater. The organic layer was dried over sodium sulfate and thenconcentrated under reduced pressure. The residue was purified by HPFCeluting with a gradient of 20-50% CMA in chloroform. The residue wasrecrystallized from acetonitrile and the mixture was filtered. Thefiltrate was concentrated under reduced pressure to provide4-[(4-chloro-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]-1-methylpiperidin-4-ol.

Part G

The material from Part F was combined with a solution of 7N ammonia inmethanol (16 mL) in a pressure vessel. The vessel was sealed and thenheated at 150° C. for 18 hours. The reaction mixture was concentratedunder reduced pressure. The residue was purified by HPFC eluting with agradient of 25-100% solution over 6 L of 30% methanol in chloroform,triturated with acetonitrile, and dried. The resulting material wasdissolved in water. The pH of the solution was adjusted to pH 2 with 1Nhydrochloric acid and then to pH 14 with 50% aqueous sodium hydroxideand then chloroform was added. The organic phase was separated andconcentrated under reduced pressure. The residue was triturated with hotchloroform and the filtered while still hot. The isolated solid wascombined with chloroform (400 mL), washed with aqueous sodiumbicarbonate (2×60 mL), dried over sodium sulfate, and concentrated underreduced pressure. The residue was dried under vacuum at 110° C. toprovide 0.33 g of4-[(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]-1-methylpiperidin-4-olas an off-white solid, mp 241-242° C. ¹H NMR (300 MHz, DMSO-d₆) δ 8.28(d, J=8.1 Hz, 1H), 7.57 (d, J=8.1 Hz, 1H), 7.36 (t, J=8.1 Hz, 1H), 7.19(t, J=8.1 Hz, 1H), 6.37, (br s, 2H), 4.60 (s, 1H), 4.54 (br s, 1H), 3.00(t, J=7.5 Hz, 2H), 2.40 (s, 2H), 2.08 (s, 3H), 2.08 (m, 2H), 1.83 (hex,J=7.5 Hz, 2H), 1.72 (m, 4H), 1.31 (br s, 1H), 1.00 (t, J=7.5 Hz, 3H); MS(APCI) m/z 354 (M+H)⁺; Anal. calcd for C₂₀H₂₇N₅O: C, 67.96; H, 7.70; N,19.81. Found: C, 67.86; H, 7.67; N, 19.85.

Example 1574-[(4-Amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]-1-methylpiperidin-4-ol

4-[(4-Amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]-1-methylpiperidin-4-olwas prepared according to the general method of Example 156 usingpropionyl chloride in lieu of butyryl chloride in Part E. The crudeproduct was triturated with chloroform. The resulting material wasdissolved in water. The pH of the solution was adjusted to pH 2 with 1Nhydrochloric acid and then to pH 14 with 50% aqueous sodium hydroxideand then chloroform was added. The mixture was filtered to provide agray solid. The organic phase from the filtrate was concentrated underreduced pressure. The residue was triturated with chloroform. Theresulting solid was combined with the gray solid, triturated withchloroform, and dried to provide pure product as a gray solid, mp233-234° C. ¹H NMR (300 MHz, DMSO-d₆) δ 8.29 (d, J=8.1 Hz, 1H), 7.58 (d,J=8.1 Hz, 1H), 7.37 (t, J=8.1 Hz, 1H), 7.19 (t, J=8.1 Hz, 1H), 6.38, (brs, 2H), 4.61 (s, 1H), 4.55 (br s, 1H), 3.05 (q, J=7.5 Hz, 2H), 2.40 (s,2H), 2.08 (s, 3H), 2.08 (m, 2H), 1.73 (m, 4H), 1.32 (br s, 1H), 1.35 (t,J=7.5 Hz, 3H); MS (APCI) m/z 340 (M+H)⁺; Anal. calcd for C₁₉H₂₅N₅O: C,67.23; H, 7.42; N, 20.63. Found: C, 66.91; H, 7.70; N, 20.66.

Example 1584-[(4-Amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]-1-methylpiperidin-4-ol

4-[(4-Amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]-1-methylpiperidin-4-olwas prepared according to the general method of Example 156 usingethoxyacetyl chloride in lieu of butyryl chloride in Part E. The crudeproduct was triturated with hot acetonitrile; the mixture was allowed tocool and a solid was isolated by filtration. The solid was dissolved inwater. The pH of the solution was adjusted to pH 2 with 1N hydrochloricacid and then to pH 14 with 50% aqueous sodium hydroxide and thenchloroform was added. The organic phase was separated and concentratedunder reduced pressure to provide a yellow solid. This material wasrecrystallized from acetonitrile and then dried under vacuum at 105° C.to provide pure product as a light brown solid, mp 197.5-198.5° C. ¹HNMR (300 MHz, DMSO-d₆) δ 8.30 (d, J=8.1 Hz, 1H), 7.59 (d, J=8.1 Hz, 1H),7.40 (t, J=6.9 Hz, 1H), 7.21 (t, J=6.9 Hz, 1H), 6.54, (br s, 2H), 4.88(br s, 2H), 4.71 (s, 2H), 4.67 (br s, 1H), 3.51 (q, J=6.9 Hz, 2H), 2.40(m, 2H), 2.08 (s, 3H), 2.08 (m, 2H), 1.76 (m, 2H), 1.30 (br s, 2H), 1.13(t, J=6.9 Hz, 3H); MS (APCI) m/z 370 (M+H)⁺; Anal. calcd for C₂₀H₂₇N₅O₂:C, 65.02; H, 7.37; N, 18.96. Found: C, 64.75; H, 7.45; N, 19.15.

Example 1592-Ethoxymethyl-1-({4-[2-(methylsulfonyl)ethoxy]tetrahydro-2H-pyran-4-yl}methyl)-1H-imidazo[4,5-c]quinolin-4-amine

4-[(2-Ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]tetrahydro-2H-pyran-4-ol(4.05 g, Example 10 Parts A through E) was converted to2-ethoxymethyl-1-({4-[2-(methylsulfonyl)ethoxy]tetrahydro-2H-pyran-4-yl}methyl)-1H-imidazo[4,5-c]quinolin-4-amineaccording to the general methods of Example 13 using4-[(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]tetrahydro-2H-pyran-4-olin lieu of tert-butyl[(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]-4-hydroxyypiperidine-1-carboxylatein Part A. The crude product was purified by column chromatography(silica gel eluting with 95/5 dichloromethane/methanol) to provide awhite foam. This material was recrystallized from acetonitrile, isolatedby filtration, washed with acetonitrile, and then dried under vacuum at65° C. to provide 50 mg of pure product as a white powder. MS (APCI) m/z463 (M+H)⁺; Anal. Cacld for C₂₂H₃₀N₄O₅S: C, 57.12; H, 6.54; N, 12.11.Found: C, 57.08; H, 6.75; N, 12.04.

Example 1603-[(4-Amino-2-propyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]tetrahydrofuran-3-ol

Part A

Pyridinium chlorochromate (85.8 g, 3.5 eq) was added in portions over aperiod of 5 minutes to a solution of 3-hydroxytetrahydrofuran (10.02 g,1.0 eq) in dichloromethane (115 mL). The reaction mixture was stirred atambient temperature for 3.5 hours and then applied directly to a columnof silica gel (325 g). The column was eluted with diethyl ether. Thefractions containing product were combined and the solvent was removedby atmospheric distillation to provide 5.22 g of tetrahydrofuran-3-one.

Part B

Potassium cyanide (50 mg, 0.02 eq.) and 18-crown-6 macrocyclic polyether(203 mg, 0.02 eq) were dissolved in methanol (8 mL). The solution wasstirred for 5 minutes and then concentrated under reduced pressure. Theresulting white solid was dissolved in trimethylsilyl cyanide (5.5 mL,1.0 eq.) and the solution was added dropwise over a period of 1 minuteto the material from Part A (1.0 eq). The reaction was cooled with anice bath during the addition. The reaction mixture was stirred in theice bath for 2 minutes, allowed to warm to ambient temperature, andstirred for 15 minutes.

Part C

The reaction mixture from Part B (1.0 eq) was diluted withtetrahydrofuran (THF) and cooled to 0° C. Solid lithium aluminum hydride(1.46 g, 1.0 eq) was added in portions over a period of 5 minutes. After1 hour water (1.5 mL) was added dropwise; the ice bath was removed, andthe reaction was stirred for several minutes. Sodium hydroxide (1.5 mLof 10%) and water (4.5 mL) were added and the reaction mixture wasstirred for 30 minutes. Magnesium sulfate was added and the reactionmixture was stirred for another 10 minutes. The reaction mixture wasfiltered through a layer of CELITE filter aid. The filter cake wasrinsed with THF (2×100 mL). The filtrate was concentrated under vacuumto provide a light yellow liquid. This material was concentrated fromacetonitrile (2×100 mL) to provide 5.19 g of a mixture of3-(aminomethyl)tetrahydrofuran-3-ol and(3-trimethylsilyloxytetrahydrofuran-3-yl)methylamine.

Part D

4-Chloro-3-nitronaphthyridine (7.13 g, 1.1 eq) and triethylamine (5.21mL, 1.1 eq) were added sequentially to a solution of the material fromPart C (1.0 eq) in dichloromethane (113 mL). The reaction mixture wascooled briefly with an ice bath to control an exotherm and then stirredat ambient temperature overnight. The reaction mixture was diluted withwater (200 mL) and dichloromethane (350 mL). The aqueous layer wasextracted with dichloromethane (400 mL). The combined organics weredried over magnesium sulfate and then concentrated under reducedpressure to provide 10.96 g of a yellow solid. This material wasdissolved in methanol (350 mL). Potassium carbonate (5.0 g) was added;the resulting suspension was stirred for 20 minutes and thenconcentrated under reduced pressure. The residue was slurried with water(130 mL) overnight and then filtered. The isolated solid was rinsed withwater (2×70 mL) and dried under vacuum to provide 8.27 g of3-[3-nitro[1,5]napthyridin-4-yl)methyl]tetrahydrofuran-3-ol as a yellowsolid.

Part E

A suspension of3-[3-nitro[1,5]napthyridin-4-yl)methyl]tetrahydrofuran-3-ol (2.00 g) and10% palladium on carbon (200 mg) in ethanol (68 mL) was placed underhydrogen pressure (50 psi, 3.4×10⁵ Pa) on a Parr apparatus for 4 hours.The reaction mixture was sparged with nitrogen for 15 minutes and thenfiltered through a layer of CELITE filter aid. The filtrate wasconcentrated under reduced pressure. The residue was reconcentrated fromacetonitrile (2×75 mL) and dichloromethane (2×50 mL) and then driedunder high vacuum to provide 1.79 g of3-[3-amino[1,5]napthyridin-4-yl)methyl]tetrahydrofuran-3-ol as a yellowfoam.

Part F

Toluene (29 mL), trimethyl orthobutyrate (0.56 mL, 1.1 eq), and pyridinehydrochloride (37 mg, 0.1 eq) were added to a suspension of3-[3-amino[1,5]napthyridin-4-yl)methyl]tetrahydrofuran-3-ol (0.83 g, 1.0eq) in chloroform (3 mL). The reaction mixture was heated at reflux withstirring for 16 hours, allowed to cool to ambient temperature, and thenconcentrated under reduced pressure. The residue was triturated withacetonitrile (about 6 mL) and filtered. The isolated solid was rinsedwith acetonitrile (3×4 mL) to provide 0.80 g of a tan solid. A portion(112 mg) was purified by HPFC (silica gel eluting with 20% CMA inchloroform) to provide 88 mg of3-[(2-propyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]tetrahydrofuran-3-olas light tan needles, mp 151-152° C. ¹H NMR (300 MHz, DMSO-d₆): δ 9.25(s, 1H), 8.96 (dd, J=1.6, 4.3 Hz, 1H), 8.51 (dd, J=1.6, 8.5 Hz, 1H),7.73 (dd, J=4.3, 8.5 Hz, 1H), 5.37 (s, 1H), 5.30 (m, 1H), 5.08 (m, 1H),3.80 (m, 3H), 3.46 (d, J=8.9 Hz, 1H), 3.12 (t, J=7.5 Hz, 2H), 2.12 (m,1H), 1.91 (m, 2H), 1.66 (m, 1H), 1.03 (t, J=7.4 Hz, 3H); MS (APCI) m/z313 (M+H)⁺; Anal. calcd for C₁₇H₂₀N₄O₂: C, 65.37; H, 6.45; N, 17.94.Found: C, 65.13; H, 6.18; N, 17.88.

Part G

3-Chloroperbenzoic acid (0.60 g of 77%, 1.1 eq) was added to a solutionof3-[(2-propyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]tetrahydrofuran-3-ol(0.68 g, 1.0 eq) in chloroform. The reaction mixture was stirred atambient temperature for 3.5 hours. Ammonium hydroxide (22 mL) andp-toluenesulfonyl chloride (0.50 g, 1.2 eq) were added sequentially andthe reaction mixture was stirred at ambient temperature for 2 hours. Thereaction mixture was diluted with water (20 mL) and chloroform (30 mL).The aqueous layer was extracted with chloroform (30 mL). The combinedorganics were dried over magnesium sulfate and then concentrated underreduced pressure to provide a brown foam. This material was trituratedwith ethyl acetate (about 12 mL). A solid was isolated by filtration,rinsed with ethyl acetate (4×5 mL), and then dried under vacuum toprovide 383 mg of a yellow solid. This material was triturated with warmethyl acetate (about 15 mL). A solid was isolated by filtration, rinsedwith ethyl acetate (3×5 mL), and then dried under vacuum to provide 260mg of3-[(4-amino-2-propyl-1H-imidazo[4,5-c][1,5]-naphthyridin-1-yl)methyl]tetrahydrofuran-3-olas a tan powder, mp 171-173° C. ¹H NMR (300 MHz, DMSO-d₆): δ 8.47 (dd,J=1.5, 4.3 Hz, 1H), 7.91 (dd, J=1.5, 8.4 Hz, 1H), 7.43 (dd, 1H), 6.75(s, 2H), 5.46 (s, 1H), 5.22 (m, 1H), 4.98 (m, 1H), 3.80 (m, 3H), 3.45(d, J=8.9 Hz, 1H), 3.04 (t, J=7.6 Hz, 2H), 2.09 (m, 1H), 1.85 (sextet,J=7.5 Hz, 2H), 1.66 (m, 1H), 1.01 (t, J=7.4 Hz, 3H); MS (APCI) m/z 328(M+H)⁺; Anal. calcd for C₁₇H₂₁N₅O₂: C, 62.37; H, 6.47; N, 21.39. Found:C, 62.14; H, 6.33; N, 21.31.

Example 1613-[(4-Amino-2-ethyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]tetrahydrofuran-3-ol

Part A

3-[(2-ethyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]tetrahydrofuran-3-olwas prepared according to the methods of Parts A through F in Example160 using triethyl orthoformate in lieu of trimethyl orthobutyrate inPart F. The crude product was triturated with ethyl acetate (about 6mL). A solid was isolated by filtration, rinsed with ethyl acetate (4×5mL), and then dried under vacuum to provide 839 mg of a tan powder.

Part B

The material from Part A was oxidized and then aminated according to themethods of Part G of Example 160. The crude product was triturated withethyl acetate (about 15 mL). A solid was isolated by filtration, rinsedwith ethyl acetate, and then dried under vacuum to provide 610 mg of alight orange solid. This material was recrystallized from acetonitrile(about 60 mL), isolated by filtration, rinsed with acetonitrile (3×10mL), and then dried under high vacuum to provide 462 mg of3-[(4-amino-2-ethyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]tetrahydrofuran-3-olas off white needles, mp 234-236° C. ¹H NMR (300 MHz, DMSO-d₆): δ 8.47(dd, J=1.6, 4.3 Hz, 1H), 7.92 (dd, J=1.6, 8.4 Hz, 1H), 7.43 (dd, J=4.3,8.4 Hz, 1H), 6.76 (s, 2H), 5.47 (s, 1H), 5.21 (m, 1H), 4.97 (m, 1H),3.79 (m, 3H), 3.45 (d, J=8.9 Hz, 1H), 3.08 (q, J=7.5 Hz, 2H), 2.11 (m,1H), 1.66 (m, 1H), 1.37 (t, J=7.5 Hz, 3H); MS (APCI) m/z 314 (M+H)⁺;Anal. calcd for C₁₆H₁₉N₅O₂: C, 61.33; H, 6.11; N, 22.35. Found: C,61.27; H, 6.02; N, 22.58.

Example 1623-{[4-Amino-2-(fluoromethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]methyl}tetrahydrofuran-3-ol

Part A

Fluoroacetyl chloride (0.36 mL, 1.1 eq) was added dropwise over a periodof 2 minutes to a chilled (0° C. suspension of3-[3-amino[1,5]napthyridin-4-yl)methyl]tetrahydrofuran-3-ol (1.14 g, 1.0eq) in dichloromethane (44 mL). After 30 minutes the reaction mixturewas allowed to warm to ambient temperature. The reaction mixture wasstirred for an additional 30 minutes and was then concentrated underreduced pressure to provide2-fluoro-N-(4-{[(3-hydroxytetrahydrofuran-3-yl)methyl]amino}[1,5]naphthyridin-3-yl)acetamidehydrochloride as a yellow foam.

Part B

Triethylamine (1.83 mL, 3.0 eq) was added to a suspension of thematerial from Part A (1.0 eq) in ethanol (30 mL). The reaction mixturewas heated at 70° C. for 2.5 hours and then at reflux for another hour.The reaction mixture was allowed to cool to ambient temperature and thenconcentrated under reduced pressure. The residue was suspended in 10%CMA in chloroform, filtered through a cotton plug to remove solids, andthen purified by chromatography eluting with 10% CMA in chloroform for 2column volumes, with a gradient of 10-25% CMA for 8 column volumes, andfinally with 25% CMA in chloroform for 4 column volumes to provide 0.69g of3-{[2-(fluoromethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]methyl}tetrahydrofuran-3-ol.

Part C

The material from Part B was oxidized and then aminated according to themethods of Part G of Example 160. The crude product was triturated withethyl acetate (about 8 mL). A solid was isolated by filtration, rinsedwith ethyl acetate (4×56 mL), and then dried under vacuum to provide 345mg of an orange foam. This material was dissolved in hot 20% CMA inchloroform (10 mL) and then purified by chromatography eluting with 20%CMA in chloroform for 8 column volumes to provide 270 mg of an off whitesolid. This material was triturated with ethyl acetate (about 8 mL). Asolid was isolated by filtration, rinsed with ethyl acetate (2×2 mL),and then dried under vacuum to provide 196 mg of3-{[4-amino-2-(fluoromethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]methyl}tetrahydrofuran-3-olas an off white powder, mp 209-210° C. ¹H NMR (300 MHz, DMSO-d₆): δ 8.51(dd, J=1.5, 4.3 Hz, 1H), 7.94 (dd, J=1.5, 8.4 Hz, 1H), 7.49 (dd, J=4.3,8.4 Hz, 1H), 7.00 (br s, 2H), 5.86 (m, 2H), 5.54 (s, 1H), 5.36 (d,J=14.3 Hz, 1H), 5.10 (d, J=14.3 Hz, 1H), 3.82 (m, 3H), 3.43 (d, J=9.0Hz, 1H), 2.14 (ddd, J=8.5, 8.5, 12.6 Hz, 1H), 1.62 (m, 1H); MS (APCI)m/z 318 (M+H)⁺; Anal. calcd for C₁₅H₁₆FN₅O₂.0.38 H₂O: C, 55.58; H, 5.21;N, 21.60. Found: C, 55.96; H, 4.89; N, 21.72.

Example 1633-{[4-Amino-2-(fluoromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}tetrahydrofuran-3-ol

Part A

A mixture of 3-[3-nitroquinolin-4-yl)methyl]tetrahydrofuran-3-ol (2.5 g,Parts A through D of Example 160 using 4-chloro-3-nitroquinoline in lieuof 4-chloro-3-nitro[1,5]naphthyridine in Part D), 5% platinum on carbon(0.25 g), and ethyl acetate (150 mL) was placed under hydrogen pressure(40 psi, 2.8×10⁵ Pa) on a Parr apparatus for 4 hours. The reactionmixture was filtered through a layer of CELITE filter aid. The filtratewas concentrated under reduced pressure and then dried under high vacuumto provide 2.20 g of 3-[3-aminoquinolin-4-yl)methyl]tetrahydrofuran-3-olas a brown foam.

Part B

Fluoroacetyl chloride (0.578 g, 1.2 eq) was added dropwise over a periodof 3 minutes to a chilled (0° C. suspension of3-[3-aminoquinolin-4-yl)methyl]tetrahydrofuran-3-ol (1.3 g, 1.0 eq) indichloromethane (50 mL). After 30 minutes the reaction mixture wasallowed to warm to ambient temperature. The reaction mixture was stirredovernight at ambient temperature and then concentrated under reducedpressure to provide2-fluoro-N-(4-{[(3-hydroxytetrahydrofuran-3-yl)methyl]amino}quinolin-3-yl)acetamidehydrochloride as a brown solid.

Part C

Triethylamine (2.1 mL, 3.0 eq) was added to a mixture of the materialfrom Part B (1.0 eq) and methanol (50 mL). The reaction mixture washeated at 80° C. for 2 hours, allowed to cool to ambient temperature,and then concentrated under reduced pressure to provide a brown solid.This material was combined with the product from another run, dissolvedin chloroform, and purified by HPFC eluting with a gradient of 0-50% CMAin chloroform for 600 mL and then with 50% CMA in chloroform for 1200 mLto provide 800 mg of3-{[2-(fluoromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}tetrahydrofuran-3-olas an orange solid.

Part D

The material from Part D was oxidized and then aminated according to themethods of Part G of Example 160. The crude product was triturated withchloroform and then filtered. The filtrate was concentrated underreduced pressure. The residue was purified by HPFC eluting sequentiallywith chloroform for 4 column volumes, a gradient of 0-50% CMA inchloroform for 6 column volumes, and 50% CMA in chloroform for 6 columnvolumes to provide a yellow solid. This material was triturated withmethanol. A solid was isolated by filtration and dried under high vacuumto provide 148 mg of3-{[4-amino-2-(fluoromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}tetrahydrofuran-3-olas a light orange solid, mp 169-171° C. ¹H NMR (300 MHz, DMSO-d₆): 8.30(d, J=7.9 Hz, 1H), 7.61 (dd, J=8.3, 1.1 Hz, 1H), 7.45 (dt, J=7.5, 0.8Hz, 1H), 7.23 (t, J=7.6, 1.1 Hz, 1H), 6.67 (s, 2H), 5.83 (d, J=48.0 Hz,2H), 5.48 (s, 1H), 4.89 (s, 2H), 3.83 (m, 2H), 3.59 (dd, J=103.8, 9.1Hz, 2H), 1.91 (m, 2H); MS (EI) m/z 316 (M+H)⁺; Anal. calcd forC₁₆H₁₇FN₄O₂.0.58 H₂O: C, 58.81; H, 5.60; N, 17.14. Found: C, 58.92; H,5.72; N, 17.01.

Example 1643-[(4-Amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]tetrahydrofuran-3-ol

Part A

3-[(2-Propyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]tetrahydrofuran-3-olwas prepared using the method of Part F of Example 160 using3-[3-aminoquinolin-4-yl)methyl]tetrahydrofuran-3-ol in lieu of3-[3-amino[1,5]napthyridin-4-yl)methyl]tetrahydrofuran-3-ol. The crudeproduct was triturated with acetonitrile (about 10 mL) to provide 500 mgof pure product. An additional 190 mg was isolated from the filtrate.

Part B

The material from Part A was oxidized and then aminated according to themethods of Part G of Example 160. The crude product was triturated withchloroform and then filtered. The filtrate was concentrated underreduced pressure. The residue was purified by HPFC eluting sequentiallywith chloroform for 3 column volumes and a gradient of 0-50% CMA inchloroform for 10 column volumes to provide a yellow-orange solid. Thismaterial was triturated with methanol. A solid was isolated byfiltration. This material was triturated with 10% aqueous sodiumhydroxide (10 mL) to provide an orange solid. This material was combinedwith acetonitrile, heated to reflux, and then allowed to cool to ambienttemperature. A solid was isolated by filtration and dried under highvacuum to provide3-[(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]tetrahydrofuran-3-olas a tan solid, mp 201-203° C. ¹H NMR (300 MHz, DMSO-d₆): 8.25 (d, J=7.4Hz, 1H), 7.59 (dd, J=8.3, 1.1 Hz, 1H), 7.38 (t, J=7.7 Hz, 1H), 7.19 (td,J=7.6, 1.2 Hz, 1H), 6.41 (s, 2H), 5.33 (s, 1H), 4.75 (s, 2H), 3.80 (m,2H), 3.58 (dd, J=73.4, 9.0 Hz, 2H), 2.98 (t, J=7.4 Hz, 2H), 1.94 (m,2H), 1.83 (m, J=7.5 Hz, 2H), 1.01 (t, J=7.4 Hz, 3H); MS (EI) m/z 327(M+H)⁺; Anal. calcd for C₁₈H₂₂N₄O₂: C, 66.24; H, 6.79; N, 17.17. Found:C, 65.86; H, 6.82; N, 17.25.

Example 1653-[(4-Amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]tetrahydrofuran-3-ol

Part A

3-[(2-Ethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]tetrahydrofuran-3-olwas prepared using the method of Part F of Example 160 using3-[3-aminoquinolin-4-yl)methyl]tetrahydrofuran-3-ol in lieu of3-[3-amino[1,5]napthyridin-4-yl)methyl]tetrahydrofuran-3-ol andtrimethyl orthopropionate in lieu of trimethyl orthobutyrate. The crudeproduct was triturated with acetonitrile (about 10 mL) to provide 737 mgof pure product. An additional 210 mg was isolated from the filtrate.

Part B

The material from Part A was oxidized and then aminated according to themethods of Part G of Example 160. The crude product was triturated withacetonitrile (about 2 mL) to provide a tan solid. This material wascombined with the material from another run and dissolved in refluxingacetonitrile (50 mL). The solution was filtered and then cooled to −20°C. A solid was isolated by filtration and then dried under high vacuumto provide3-[(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]tetrahydrofuran-3-olas a light tan solid, mp 245-247° C. ¹H NMR (300 MHz, DMSO-d₆): 8.25 (d,J=7.6 Hz, 1H), 7.59 (dd, J=8.3, 1.2 Hz, 1H), 7.38 (t, J=7.6, 1.0 Hz,1H), 7.19 (t, J=7.6, 1.2 Hz, 1H), 6.41 (s, 2H), 5.33 (s, 1H), 4.75 (s,2H), 3.81 (m, 2H), 3.58 (dd, J=75.4, 9.0 Hz, 2H), 3.02 (q, J=7.4 Hz,2H), 1.89 (m, 2H), 1.36 (t, J=7.4 Hz, 3H); MS (EI) m/z 312 (M+H)⁺; Anal.calcd for C₁₇H₂₀N₄O₂: C, 65.37; H, 6.45; N, 17.94. Found: C, 65.30; H,6.29; N, 18.00.

Example 1663-[(4-Amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]tetrahydrofuran-3-ol

Part A

3-[(2-Methyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]tetrahydrofuran-3-olwas prepared using the method of Part F of Example 160 using3-[3-aminoquinolin-4-yl)methyl]tetrahydrofuran-3-ol in lieu of3-[3-amino[1,5]napthyridin-4-yl)methyl]tetrahydrofuran-3-ol andtrimethyl orthoacetate in lieu of trimethyl orthobutyrate. The crudeproduct was dissolved in chloroform and purified by HPFC eluting withchloroform for 3 column volumes and then with a gradient of 0-50% CMA inchloroform for 8 column volumes to provide 0.87 g of product as an offwhite foam.

Part B

The material from Part A was oxidized and then aminated according to themethods of Part G of Example 160. The crude product was isolated byfiltration and triturated with 10% sodium hydroxide. The resulting solidwas isolated by filtration, rinsed with water, and then refluxed withacetonitrile. The purification procedure was repeated and the resultingsolid was isolated by filtration and then dried under high vacuum toprovide3-[(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]tetrahydrofuran-3-olas a light tan solid, mp 278° C. (dec). ¹H NMR (300 MHz, DMSO-d₆): 8.24(d, J=8.0 Hz, 1H), 7.59 (d, J=8.7 Hz, 1H), 7.38 (t, J=7.4 Hz, 1H), 7.19(t, J=7.2 Hz, 1H), 6.45 (s, 2H), 5.36 (s, 1H), 4.74 (s, 2H), 3.82 (m,2H), 3.50 (dd, J=77.6, 9.0 Hz, 2H), 2.65 (s, 3H), 1.92 (m, 2H); MS (EI)m/z 298 (M+H)⁺; Anal. calcd for C₁₆H₁₈N₄O₂.0.52 H₂O: C, 62.45; H, 6.24;N, 18.21. Found: C, 62.39; H, 5.95; N, 17.81.

Examples 167-190 Part A

A suspension of 1-aminomethyl-1-cyclohexanol hydrochloride (20.0 g, 121mmol) and 4-chloro-3-nitroquinoline (24.0 g, 115 mmol) indichloromethane (550 mL) was cooled to 0° C., and triethylamine (40 mL,290 mmol) was added dropwise over a period of 30 minutes. The reactionwas allowed to warm to room temperature over two hours. An analysis byHPLC indicated that the 4-chloro-3-nitroquinoline starting materialactually contained some 3-nitroquinolin-4-ol, and additional pure4-chloro-3-nitroquinoline (12.0 g, 57.5 mmol) was added. The reactionwas stirred for four hours, and additional 1-aminomethyl-1-cyclohexanolhydrochloride (2.0 g, 12 mmol) was added, and the resulting suspensionwas stirred for three days. The solvent was removed under reducedpressure, and the residue was triturated in water for one hour andisolated by filtration. The resulting solid was triturated with hotdichloromethane and isolated by filtration from the hot mixture toprovide 36.5 g of 1-{[(3-nitroquinolin-4-yl)amino]methyl}cyclohexanol asa bright yellow powder.

Part B

A suspension of 1-{[(3-nitroquinolin-4-yl)amino]methyl}cyclohexanol(15.0 g, 49.8 mmol) in ethyl acetate (225 mL) in a Parr vessel waspurged with nitrogen; 5% platinum on carbon (1.5 g) was added. Thereaction was placed under hydrogen pressure (35 psi, 2.4×10⁵ Pa) for 3.5hours and then filtered through a layer of CELITE filter agent. Thefilter cake was washed with ethyl acetate (100 mL), and the filtrate wasconcentrated under reduced pressure to provide1-{[(3-aminoquinolin-4-yl)amino]methyl}cyclohexanol as a yellow solid.

Part C

A solution of the material from Part B in dichloromethane (200 mL) wascooled to 0° C., and chloroacetyl chloride (4.4 mL, 55 mmol) was addedover a period of ten minutes. The reaction was stirred for one hour at0° C. and then concentrated under reduced pressure to provide2-chloro-N-(4-{[(1-hydroxycyclohexyl)methyl]amino}quinolin-3-yl)acetamidehydrochloride as a yellow solid.

Part D

Triethylamine (21 mL, 150 mmol) was added to a solution of the materialfrom Part C in ethanol (200 mL), and the reaction was heated at 60° C.for four hours. The solvent was removed under reduced pressure, and theresidue was partitioned between dichloromethane (150 mL) and saturatedaqueous sodium bicarbonate (125 mL). The aqueous layer was separated andextracted with dichloromethane (2×50 mL), and the combined organicfractions were dried over magnesium sulfate, filtered, and concentratedunder reduced pressure to provide 14.2 g of an orange solid. The solidwas triturated with acetonitrile and isolated by filtration to provide10.74 g of1-{[2-(chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexanolas a pale yellow solid.

Part E

3-Chloroperoxybenzoic acid (8.37 g of 70% pure material, 34 mmol) wasadded to a suspension of1-{[2-(chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexanol(8.0 g, 24 mmol) in chloroform (100 mL), and the reaction was stirred atroom temperature for four hours. Saturated aqueous sodium bicarbonate(100 mL) was added, and the mixture was stirred for 15 minutes. Aprecipitate formed and was isolated by filtration to provide1-{[2-(chloromethyl)-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexanolas a white solid.

Part F

Ammonium hydroxide (8 mL of 15 M) was added to a suspension of thematerial from Part E in methanol (100 mL). The mixture was cooled to 0°C., and benzenesulfonyl chloride (6.5 mL, 51 mmol) was added dropwiseover a period of eight minutes. The reaction was stirred at 0° C. forone hour, and an analysis by HPLC indicated the presence of startingmaterial. Additional benzenesulfonyl chloride (6.5 mL, 51 mmol) wasadded in two portions over two hours. The reaction was allowed to warmto room temperature slowly and stirred overnight. A precipitate waspresent and was isolated by filtration, stirred with saturated aqueoussodium bicarbonate (100 mL), isolated by filtration, washed with water(50 mL), and dried to provide 6.14 g of1-{[4-amino-2-(chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexanol.

Part G

Potassium phthalimide (2.59 g, 14.0 mmol) was added to a solution of1-{[4-amino-2-(chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexanol(5.07 g, 13.3 mmol) in DMF (50 mL), and the reaction mixture was stirredat room temperature overnight. An analysis by HPLC indicated thepresence of starting material, and additional potassium phthalimide (1g) was added. The reaction was stirred for an additional five hours, andthen concentrated under reduced pressure. The residue was trituratedwith methanol, and the resulting white solid was isolated by filtration.The filtrate was concentrated under reduced pressure, and the residuewas triturated with methanol to afford additional white solid, which wasisolated by filtration. The two solids were combined to provide2-({4-amino-1-[(1-hydroxycyclohexyl)methyl]-1H-imidazo[4,5-c]quinolin-2-yl}methyl)-1H-isoindole-1,3(2H)-dione.

Part H

Hydrazine (2.1 mL, 66 mmol) was added to a suspension of the materialfrom Part G in ethanol (50 mL), and the reaction was stirred for 24hours at room temperature. The ethanol was removed under reducedpressure, and the resulting white solid was sonicated with hydrochloricacid (50 mL of 1M). The resulting suspension was filtered to remove asolid, and the filtrate was adjusted to pH 8 with the addition of solidsodium bicarbonate. A precipitate formed and was isolated by filtrationand dried at 50° C. overnight in a vacuum oven to provide 2.99 g of1-{[4-amino-2-(aminomethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexanolas a white powder.

Part I

A reagent (0.11 mmol, 1.1 equivalents) from the table below was added toa test tube containing1-{[4-amino-2-(aminomethyl)-1H-imidazo[4,5-c]quinoline-1-yl]methyl}cyclohexanol(33 mg, 0.10 mmol) and N,N-diisopropylethylamine (0.035 mL, 0.20 mmol)in N,N-dimethylacetamide (DMA) (1 mL). The test tube was capped andshaken overnight at ambient temperature. The solvent was then removed byvacuum centrifugation.

The compounds were purified by prep HPLC according to the methoddescribed in Examples 16-53. The table below shows the reagent added toeach test tube, the structure of the resulting compound, and theobserved accurate mass for the isolated trifluoroacetate salt.

Measured Mass Example Reagent R (M + H) 167 Propionyl chloride

382.2239 168 Methyl chloroformate

384.2025 169 Cyclopropane- carbonyl chloride

394.2232 170 Butyryl chloride

396.2399 171 Isobutyryl chloride

396.2392 172 Cyclobutanecarbonyl chloride

408.2421 173 Benzoyl chloride

430.2243 174 2-Chlorobenzoyl chloride

464.1848 175 3-Chlorobenzoyl chloride

464.1852 176 Isonicotinoyl chloride hydrochloride

431.2201 177 Nicotinoyl chloride hydrochloride

431.2199 178 Picolinoyl chloride hydrochloride

431.2203 179 trans-2-Phenyl-1- Cyclopropane- carbonyl chloride

470.2561 180 3,4-Dichlorobenzoyl chloride

498.1449 181 Methanesulfonyl chloride

404.1746 182 Ethanesulfonyl chloride

418.1910 183 1-Propanesulfonyl chloride

432.2058 184 Isopropylsulfonyl chloride

432.2075 185 Dimethylsulfamoyl chloride

433.2028 186 Benzenesulfonyl chloride

466.1906 187 1-Methylimidazole-4- sulfonyl chloride

470.1980 188 alpha- Toluenesulfonyl chloride

480.2076 189 3-Chlorobenzene- sulfonyl chloride

500.1516 190 4-Chlorobenzene- sulfonyl chloride

500.1518

Examples 191-205 Part A

Under a nitrogen atmosphere, nitromethane (116 mL, 2.14 mol) and sodiumethoxide (2.6 g of 96% pure material, 36 mmol) were sequentially addedto a solution of cyclobutanone (50.0 g, 713 mmol) in ethanol (71 mL),and the resulting solution was stirred at room temperature for 4 days.Some of the ethanol was removed under reduced pressure, and water (100mL) was added. The resulting mixture was extracted with ethyl acetate(3×150 mL). The combined extracts were washed sequentially with water(2×80 mL) and brine (40 mL), dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The residue was purified by vacuumdistillation under high vacuum at 70° C. to provide 46.1 g of1-(nitromethyl)cyclobutanol as an orange liquid.

Part B

A mixture of 1-(nitromethyl)cyclobutanol (46.0 g, 351 mmol), 20%palladium hydroxide on carbon (6.9 g) and ethanol (1 L) was placed underhydrogen pressure (30 psi, 2.1×10⁵ Pa) on a Parr apparatus for two days.An analysis by nuclear magnetic resonance spectroscopy indicated thereaction was incomplete, and additional 20% palladium hydroxide oncarbon (5 g) was added. The reaction was placed under hydrogen pressure(30 psi, 2.1×10⁵ Pa) for four days. The reaction mixture was filteredthrough a layer of CELITE filter agent, and the filter cake was washedwith methanol. The filtrate was concentrated under reduced pressure toprovide 34.8 g of 1-(aminomethyl)cyclobutanol as a white solid.

Part C

A solution of 4-chloro-3-nitroquinoline (30.0 g, 144 mmol) indichloromethane (350 mL) was cooled to 0° C. under a nitrogenatmosphere, and triethylamine (22.1 mL, 158 mmol) was added. A solutionof 1-(aminomethyl)cyclobutanol (16.0 g, 158 mmol) in dichloromethane(130 mL) was then added over a period of one hour, followed by a rinseof dichloromethane (100 mL). The reaction was stirred at roomtemperature overnight. The solvent was removed under reduced pressure,and the residue was triturated in water (500 mL) and saturated aqueoussodium bicarbonate (200 mL) for two hours. A solid was present and wasisolated by filtration, washed with a large amount of water, and driedin a vacuum oven at 55° C. to provide 38.7 g of1-{[(3-nitroquinolin-4-yl)amino]methyl}cyclobutanol as a yellow solid.

Part D

1-{[(3-Nitroquinolin-4-yl)amino]methyl}cyclobutanol (14.0 g, 51.2 mmol)was hydrogenated (50 psi, 3.5×10⁵ Pa) according to the method describedin Part B of Examples 167-190 to provide1-{[(3-aminoquinolin-4-yl)amino]methyl}cyclobutanol as a yellow solid.

Part E

A solution of the material from Part D in dichloromethane (250 mL) wascooled to 0° C., and chloroacetyl chloride (4.50 mL, 56.4 mmol) wasadded over a period of 15 minutes. The reaction was allowed to warm toroom temperature and stirred for four hours. An analysis by LC/MSindicated the presence of starting material, and additional chloroacetylchloride (1 mL) was added. The reaction was stirred overnight at roomtemperature and then concentrated under reduced pressure to provide2-chloro-N-(4-{[(1-hydroxycyclobutyl)methyl]amino}quinolin-3-yl)acetamidehydrochloride.

Part F

The method described in Part D of Examples 167-190 was used to treat thematerial from Part E with triethylamine (21.4 mL, 154 mmol) with themodifications that the reaction was heated at 50° C. for four hours,chloroform was used in the work-up procedure, and following the work-upprocedure, the product was not purified by trituration.1-{[2-(Chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclobutanol(16.5 g) was obtained as a yellow solid containing small amounts ofchloroform and triethylamine.

Part G

3-Chloroperoxybenzoic acid (9.15 g of 70% pure material, 37.1 mmol) wasadded to a suspension of1-{[2-(chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclobutanol(8.00 g, 26.5 mmol) in chloroform (100 mL) under a nitrogen atmosphere,and the reaction was stirred at room temperature overnight. Additionalchloroform (200 mL) was added, and the solution was washed sequentiallywith saturated aqueous sodium bicarbonate (2×80 mL) and brine (20 mL),dried over magnesium sulfate, filtered, and concentrated under reducedpressure to provide1-{[2-(chloromethyl)-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclobutanolas a yellow solid.

Part H

Ammonium hydroxide (8.83 mL of 15 M) was added to a solution of thematerial from Part G in methanol (100 mL). The mixture was cooled to 0°C. under a nitrogen atmosphere, and benzenesulfonyl chloride (7.10 mL,55.7 mmol) was added dropwise over a period of eight minutes. Thereaction was stirred at 0° C. for two hours, combined with material fromanother run, and concentrated under reduced pressure. The residue wasdissolved in chloroform (300 mL), and the resulting solution was washedsequentially with saturated aqueous sodium carbonate (2×80 mL) and brine(40 mL), dried over sodium sulfate, filtered, and concentrated underreduced pressure. The crude product was purified by prep HPLC using aHORIZON HPFC system (silica cartridge, eluting with chloroform:CMA in agradient from 100:0 to 70:30) to provide 4.00 g of1-{[4-amino-2-(chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclobutanolas a yellow solid.

Part I

Under a nitrogen atmosphere, potassium phthalimide (1.21 g, 6.52 mmol)was added to a solution of1-{[4-amino-2-(chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclobutanol(1.88 g, 5.93 mmol) in DMF (30 mL), and the reaction mixture was stirredat room temperature overnight and then concentrated under reducedpressure. The residue was partitioned between chloroform (200 mL) andwater (25 mL)/saturated aqueous sodium bicarbonate (2×40 mL). Theorganic layer was washed with brine (2×40 mL), dried over sodiumsulfate, filtered, and concentrated under reduced pressure to provide2.42 g of2-({4-amino-1-[(1-hydroxycyclobutyl)methyl]-1H-imidazo[4,5-c]quinolin-2-yl}methyl)-1H-isoindole-1,3(2H)-dione.

Part J

Under a nitrogen atmosphere, hydrazine (0.89 mL, 28 mmol) was added to asuspension of2-({4-amino-1-[(1-hydroxycyclobutyl)methyl]-1H-imidazo[4,5-c]quinolin-2-yl}methyl)-1H-isoindole-1,3(2H)-dione(2.42 g, 5.66 mmol) in ethanol (57 mL), and the reaction was stirred fortwo hours at room temperature. The ethanol was removed under reducedpressure, and the resulting white solid was triturated with 2 Nhydrochloric acid. The resulting suspension was filtered to remove asolid, and the filter cake was washed with water. The filtrate was madebasic with the addition of solid sodium bicarbonate. A precipitateformed and was isolated by filtration, washed with water, and dried at50° C. for three days in a vacuum oven to provide 0.994 g of1-{[4-amino-2-(aminomethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclobutanolas a yellow solid.

Part K

A reagent (0.11 mmol, 1.1 equivalents) from the table below was added toa test tube containing1-{[4-amino-2-(aminomethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclobutanol(30 mg, 0.10 mmol) and N,N-diisopropylethylamine (0.036 mL, 0.20 mmol)in DMA (1 mL). The test tube was capped and vortexed overnight atambient temperature. Two drops of water were added to each reaction, andthe solvent was then removed by vacuum centrifugation.

The compounds were purified by prep HPLC according to the methoddescribed in Examples 16-53. The table below shows the reagent added toeach test tube, the structure of the resulting compound, and theobserved accurate mass for the isolated trifluoroacetate salt.

Measured Mass Example Reagent R (M + H) 191 Propionyl chloride

354.1905 192 Cyclopropanecarbonyl chloride

366.1926 193 Isobutyryl chloride

368.2078 194 Benzoyl chloride

402.1927 195 4-Methoxybenzoyl chloride

432.2044 196 4-Chlorobenzoyl chloride

436.1553 197 Nicotinoyl chloride hydrochloride

403.1879 198 3,4-Dichlorobenzoyl chloride

470.1158 199 Methanesulfonyl chloride

376.1445 200 Ethanesulfonyl chloride

390.1597 201 Isopropylsulfonyl chloride

404.1769 202 Dimethylsulfamoyl chloride

405.1712 203 Benzenesulfonyl chloride

438.1631 204 1-Methylimidazole- 4-sulfonyl chloride

442.1665 205 2,2,2- Trifluoroethane- sulfonyl chloride

444.1327

Examples 206-248

A reagent (0.11 mmol, 1.1 eq) from the table below was added to a testtube. A solution of4-[4-amino-2-methyl-1H-imidazo[4,5-c][1,5]napthyridin-1-yl)methyl]piperidine-4-oldihydrochloride (38 mg, 0.10 mmol, 1.0 eq. Example 125 Part A) andN,N-diisopropylethylamine (0.086 mL, 5 eq)) in DMA (1 mL) and chloroform(1 mL) was added. The test tube was capped and shaken overnight atambient temperature. The reaction was quenched with water (2 drops). Thesolvent was then removed by vacuum centrifugation.

The compounds were purified by prep HPLC according to the methoddescribed in Examples 16-53. The table below shows the reagent added toeach test tube, the structure of the resulting compound, and theobserved accurate mass for the isolated trifluoroacetate salt.

Measured Example Reagent R Mass (M + H) 206 Cyclopropanecarbonylchloride

381.2019 207 Butyryl chloride

383.2228 208 Isobutyryl chloride

383.2212 209 Cyclobutanecarbonyl chloride

395.2163 210 Cyclopentanecarbonyl chloride

409.2366 211 Benzoyl chloride

417.2057 212 Cyclohexanecarbonyl chloride

423.2545 213 3-Cyanobenzoyl chloride

442.1995 214 3-Methoxybenzoyl chloride

447.2169 215 4-Methoxybenzoyl chloride

447.2149 216 3-Chlorobenzoyl chloride

451.1666 217 4-Chlorobenzoyl chloride

451.1650 218 Isonicotinoyl chloride hydrochloride

418.1962 219 Nicotinoyl chloride hydrochloride

418.2012 220 Methanesulfonyl chloride

391.1589 221 Ethanesulfonyl chloride

405.1729 222 1-Propanesulfonyl chloride

419.1881 223 Isopropylsulfonyl chloride

419.1894 224 Dimethylsulfamoyl chloride

420.1837 225 Benzenesulfonyl chloride

453.1713 226 1-Methylimidazole-4-sulfonyl chloride

457.1778 227 3-Cyanobenzenesulfonyl chloride

478.1635 228 4-Cyanobenzenesulfonyl chloride

478.1655 229 3-Methoxybenzenesulfonyl chloride

483.1805 230 4-Methoxybenzenesulfonyl chloride

483.1801 231 3-Chlorobenzenesulfonyl chloride

487.1300 232 4-Chlorobenzenesulfonyl chloride

487.1334 233 Ethyl isocyanate

384.2174 234 Isopropyl isocyanate

398.2327 235 n-Propyl isocyanate

398.2311 236 Cyclopentyl isocyanate

424.2468 237 Phenyl isocyanate

432.2142 238 Cyclohexyl isocyanate

438.2636 239 4-Cyanophenyl isocyanate

457.2062 240 2-Methoxyphenyl isocyanate

462.2251 241 3-Methoxyphenyl isocyanate

462.2230 242 4-Methoxyphenyl isocyanate

462.2254 243 2-Chlorophenyl isocyanate

466.1767 244 3-Chlorophenyl isocyanate

466.1758 245 4-Chlorophenyl isocyanate

466.1754 246 1-Pyrrolidinecarbonyl chloride

410.2304 247 1-Piperidinecarbonyl chloride

424.2472 248 4-Morpholinylcarbonyl chloride

426.2259

Examples 249-285

A reagent (0.11 mmol, 1.1 eq) from the table below was added to a testtube. A solution of4-[4-amino-2-ethyl-1H-imidazo[4,5-c][1,5]napthyridin-1-yl)methyl]piperidine-4-oldihydrochloride (40 mg, 0.10 mmol, 1.0 eq. Example 121 Part A) andN,N-diisopropylethylamine (0.086 mL, 5 eq)) in DMA (1 mL) and chloroform(1 mL) was added. The test tube was capped and shaken overnight atambient temperature. Ammonium hydroxide (100 μL) was added to the tubeand the tube was vortexed for 4 hours. The solvent was then removed byvacuum centrifugation.

The compounds were purified by prep HPLC according to the methoddescribed in Examples 16-53. The table below shows the reagent added toeach test tube, the structure of the resulting compound, and theobserved accurate mass for the isolated trifluoroacetate salt.

Measured Example Reagent R Mass (M + H) 249 Cyclopropanecarbonylchloride

395.2208 250 Butyryl chloride

397.2383 251 Isobutyryl chloride

397.2387 252 Cyclopentanecarbonyl chloride

423.2492 253 Benzoyl chloride

431.2166 254 3-Methoxybenzoyl chloride

461.2286 255 p-Anisoyl chloride

461.2288 256 2-Chlorobenzoyl chloride

465.1803 257 3-Chlorobenzoyl chloride

465.1821 258 4-Chlorobenzoyl chloride

465.1801 259 Isonicotinoyl chloride hydrochloride

432.2170 260 Nicotinoyl chloride hydrochloride

432.2142 261 Methanesulfonyl chloride

405.1687 262 Ethanesulfonyl chloride

419.1889 263 1-Propanesulfonyl chloride

433.2048 264 Isopropylsulfonyl chloride

433.2039 265 Dimethylsulfamoyl chloride

434.1998 266 1-Butanesulfonyl chloride

447.2179 267 Benzenesulfonyl chloride

467.1826 268 1-Methylimidazole-4-sulfonyl chloride

471.1924 269 3-Methoxybenzenesulfonyl chloride

497.1972 270 4-Methoxybenzenesulfonyl chloride

497.1990 271 2-Chlorobenzenesulfonyl chloride

501.1467 272 3-Chlorobenzenesulfonyl chloride

501.1501 273 4-Chlorobenzenesulfonyl chloride

501.1434 274 Methyl isocyanate

384.2187 275 Isopropyl isocyanate

412.2495 276 N-Propyl isocyanate

412.2497 277 Cyclopentyl isocyanate

438.2639 278 Cyclohexyl isocyanate

452.2793 279 3-Methoxyphenyl isocyanate

476.2431 280 4-Methoxyphenyl isocyanate

476.2431 281 4-Chlorophenyl isocyanate

480.1892 282 1-Pyrrolidinecarbonyl chloride

424.2480 283 1-Piperidinecarbonyl chloride

438.2584 284 4-Morpholinylcarbonyl chloride

440.2442 285 4-Methyl-1- piperazinecarbonyl chloride

453.2715

Examples 286-330 Part A

Tert-Butyl{1-[(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]cyclopropyl}carbamate(3.40 g, Parts A through H of Example 92) was oxidized and then aminatedaccording to the general method of Part I of Example 12. The crudeproduct was purified by HPFC eluting with a gradient of 0-30% CMA inchloroform to provide a yellow solid. This material was recrystallizedfrom dichloromethane/hexanes to provide 2.60 g of tert-butyl{1-[(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]cyclopropyl}carbamateas a pale yellow solid.

Part B

Aqueous hydrochloric acid (6 mL of 6M) was added to a solution of thematerial from Part A in ethanol (12 mL). The reaction mixture was heatedat 50° C. for 4 hours and then concentrated under reduced pressure. Theresidue was concentrated from methanol 3 times and then triturated withacetonitrile to provide 2.43 g of1-[(1-aminocyclopropyl)methyl]-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-aminehydrochloride.

Part C

A reagent (1.1 eq) from the table below was added to a test tubecontaining a solution of1-[(1-aminocyclopropyl)methyl]-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-aminehydrochloride (33 mg, 0.010 mmol, 1 eq) and N,N-diisopropylethylamine(0.083 mL, 5 eq) in N,N-dimethylacetamide (1 mL). The test tube wascapped and shaken overnight at ambient temperature. The reaction wasquenched with water (2 drops). The solvent was then removed by vacuumcentrifugation.

The compounds were purified by prep HPLC according to the methoddescribed in Examples 16-53. The table below shows the reagent added toeach test tube, the structure of the resulting compound, and theobserved accurate mass for the isolated trifluoroacetate salt.

Measured Ex Reagent R Mass (M + H) 286 Cyclopropanecarbonyl chloride

380.2065 287 Butyryl chloride

382.2237 288 Isobutyryl chloride

382.2235 289 Cyclobutanecarbonyl chloride

394.2235 290 Cyclopentanecarbonyl chloride

408.2385 291 Benzoyl chloride

416.2090 292 Cyclohexanecarbonyl chloride

422.2563 293 Hydrocinnamoyl chloride

444.2401 294 3-Methoxybenzoyl chloride

446.2193 295 4-Methoxybenzoyl chloride

446.2207 296 3-Chlorobenzoyl chloride

450.1702 297 4-Chlorobenzoyl chloride

450.1710 298 Isonicotinoyl chloride hydrochloride

417.2043 299 Nicotinoyl chloride hydrochloride

417.2057 300 Picolinoyl chloride hydrochloride

417.2023 301 trans-2-Phenyl-1- cyclopropanecarbonyl chloride

456.2364 302 3,4-Dichlorobenzoyl chloride

484.1310 303 Methanesulfonyl chloride

390.1560 304 Ethanesulfonyl chloride

404.1773 305 1-Propanesulfonyl chloride

418.1898 306 1-Butanesulfonyl chloride

432.2047 307 Benzenesulfonyl chloride

452.1747 308 1-Methylimidazole-4- sulfonyl chloride

456.1817 309 alpha-Toluenesulfonyl chloride

466.1900 310 3-Cyanobenzenesulfonyl chloride

477.1700 311 3-Methoxybenzenesulfonyl chloride

482.1856 312 4-Methoxybenzenesulfonyl chloride

482.1843 313 3-Chlorobenzenesulfonyl chloride

486.1353 314 4-Chlorobenzenesulfonyl chloride

486.1349 315 Methyl isocyanate

369.2036 316 Ethyl isocyanate

383.2194 317 Isopropyl isocyanate

397.2347 318 N-Propyl isocyanate

397.2359 319 Cyclopentyl isocyanate

423.2502 320 Phenyl isocyanate

431.2188 321 Cyclohexyl isocyanate

437.2674 322 (R)-(+)-alpha-Methylbenzyl isocyanate

459.2507 323 (S)-(−)-alpha-Methylbenzyl isocyanate

459.2516 324 3-Methoxyphenyl isocyanate

461.2294 325 4-Methoxyphenyl isocyanate

461.2318 326 3-Chlorophenyl isocyanate

465.1809 327 4-Chlorophenyl isocyanate

465.1796 328 N,N-Dimethylcarbamoyl chloride

383.2202 329 1-Piperidinecarbonyl chloride

423.2494 330 4-Morpholinylcarbonyl chloride

425.2287

Examples 331-338 Part A

A reagent (1.1 eq) from the table below was added to a test tubecontaining a solution of1-[(1-aminocyclopropyl)methyl]-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-aminehydrochloride (3.6 mg, 0.1 mmol, 1 eq) and N,N-diisopropylethylamine(0.083 mL, 5 eq) in N,N-dimethylacetamide (1 mL). The test tube wascapped and shaken for 4 hours at ambient temperature. The solvent wasthen removed by vacuum centrifugation. The residue was purified bysolid-supported liquid-liquid extraction according to the followingprocedure. The residue was dissolved in chloroform (1 mL) and thenloaded onto diatomaceous earth that had been equilibrated with water (1mL) for 20 minutes. After 10 minutes chloroform (5 mL) was added toelute the product from the diatomaceous earth into a test tube. Thesolvent was then removed by vacuum centrifugation.

Part B

Dichloromethane (1 mL) was added to the test tube and the test tube wasshaken to bring all material into solution. The solution was cooled to0° C. Boron tribromide (400 μL of 1M in dichloromethane) was added tothe test tube. The test tube was shaken and then placed into an ice bathfor 30 minutes. The reaction mixture was stirred at ambient temperatureovernight. Methanol (1 mL) and hydrochloric acid (500 μL of 6N) wereadded to the test tube and the test tube was shaken. The solvents wereremoved by vacuum centrifugation.

The compounds were purified by prep HPLC according to the methoddescribed in Examples 16-53. The table below shows the reagent added toeach test tube, the structure of the resulting compound, and theobserved accurate mass for the isolated trifluoroacetate salt.

Measured Mass Example Reagent R (M + H) 331 Cyclopropane- carbonylchloride

352.1752 332 Benzoyl chloride

388.1777 333 Methanesulfonyl chloride

362.1293 334 Benzenesulfonyl chloride

424.1436 335 Phenyl isocyanate

403.1885 336 4-Morpholinyl- carbonyl chloride

397.1995 337 Methyl isocyanate

341.1703 338 Isopropyl isocyanate

369.2047

Examples 339-378 Part A

Trimethyl orthobutyrate (5.0 mL, 1.3 eq) and pyridine hydrochloride(0.14 g, 0.05 eq) were added to a suspension of ethyl1-[(3-aminoquinolin-4-ylamino)methyl]cyclobutyrate (24.3 mmol, 1.0 eq,prepared according to the general methods of Parts A through D ofExample 92 using 1,3-dibromopropane in lieu of 1,2-dibromoethane in PartA) in tolune (100 mL). The mixture was heated at reflux for 2 hours,allowed to cool to ambient temperature, and then concentrated underreduced pressure. The residue was triturated with acetonitrile. A solidwas isolated by filtration to provide 7.55 g of ethyl1-[(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]cyclobutyrate as awhite solid.

Part B

The material from Part A was converted to tert-butyl{1-[(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]cyclobutyl}carbamateaccording to the general methods of Parts G and H of Example 92. Thecrude product was triturated with acetonitrile to provide 4.36 g oftert-butyl{1-[(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]cyclobutyl}carbamateas a white solid.

Part C

The material from Part B was oxidized and then aminated according to thegeneral methods of Part I of Example 12. The crude product wastriturated with acetonitrile to provide 2.91 g of tert-butyl{1-[(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]cyclobutyl}carbamateas a tan powder.

Part D

Aqueous hydrochloric acid (6 mL of 6M) was added to a solution of thematerial from Part C in ethanol (12 mL). The reaction mixture was heatedat 60° C. for 8 hours and then concentrated under reduced pressure. Theresidue was concentrated from methanol 3 times and then triturated withacetonitrile to provide 2.99 g of1-[(1-aminocyclobutyl)methyl]-2-propyl-1H-imidazo[4,5-c]quinolin-4-aminehydrochloride.

Part E

A reagent (1.1 eq) from the table below was added to a test tubecontaining a solution of1-[(1-aminocyclobutyl)methyl]-2-propyl-1H-imidazo[4,5-c]quinolin-4-aminehydrochloride (42 mg, 0.010 mmol, 1 eq) and N,N-diisopropylethylamine(0.087 mL, 5 eq) in N,N-dimethylacetamide (1 mL). The test tube wascapped and shaken overnight at ambient temperature. The reaction wasquenched with water (2 drops). The solvent was then removed by vacuumcentrifugation.

The compounds were purified by prep HPLC according to the methoddescribed in Examples 16-53. The table below shows the reagent added toeach test tube, the structure of the resulting compound, and theobserved accurate mass for the isolated trifluoroacetate salt.

Measured Example Reagent R Mass (M + H) 339 Propionyl chloride

366.2293 340 Cyclopropanecarbonyl chloride

378.2281 341 Cyclobutanecarbonyl chloride

392.2454 342 Cyclopentanecarbonyl chloride

406.2603 343 Phenylacetyl chloride

428.2433 344 2-Methoxybenzoyl chloride

444.2429 345 3-Chlorobenzoyl chloride

448.1901 346 4-Chlorobenzoyl chloride

448.1914 347 Picolinoyl chloride hydrochloride

415.2257 348 3,4-Dimethoxybenzoyl chloride

474.2503 349 3,4-Dichlorobenzoyl chloride

482.1516 350 Methanesulfonyl chloride

388.1819 351 Dimethylsulfamoyl chloride

417.2081 352 1-Methylimidazole-4- sulfonyl chloride

454.2015 353 2,2,2-Trifluoroethanesulfonyl chloride

456.1696 354 3-Fluorobenzenesulfonyl chloride

468.1885 355 4-Fluorobenzenesulfonyl chloride

468.1908 356 3-Cyanobenzenesulfonyl chloride

475.1916 357 4-Cyanobenzenesulfonyl chloride

475.1931 358 4-Methoxybenzenesulfonyl chloride

480.2073 359 3-Chlorobenzenesulfonyl chloride

484.1579 360 3,4-Dimethoxybenzenesulfonyl chloride

510.2143 361 3,4-Dichlorobenzenesulfonyl chloride

518.1169 362 Ethyl isocyanate

381.2421 363 Isopropyl isocyanate

395.2561 364 n-Propyl isocyanate

395.2554 365 n-Butyl isocyanate

409.2722 366 Cyclopentyl isocyanate

421.2711 367 Phenyl isocyanate

429.2395 368 Cyclohexyl isocyanate

435.2869 369 3-Pyridyl isothiocyanate

446.2140 370 (R)-(+)-alpha- Methylbenzyl isocyanate

457.2723 371 (S)-(−)-alpha- Methylbenzyl isocyanate

457.2736 372 3-Methoxyphenyl isocyanate

459.2513 373 4-Methoxyphenyl isocyanate

459.2504 374 4-Chlorophenyl isocyanate

463.2012 375 N,N-Dimethylcarbamoyl chloride

381.2413 376 1-Piperidinecarbonyl chloride

421.2741 377 2-Oxo-1-imidazolidinecarbonyl chloride

422.2295 378 4-Morpholinylcarbonyl chloride

423.2523

Example 379 Tert-butyl3-[(4-amino-2-propyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]-3-hydroxyazetidine-1-carboxylate

Part A

A mixture of 1-benzhydrylazetidin-3-ol (5.00 g, 20.9 mmol, preparedaccording to A. G. Anderson, Jr. and R. Lok, J. Org. Chem., 37, 3953(1972)), ammonium formate (6.59 g, 104.5 mmol), and 10% palladium oncarbon (1.00 g) in ethanol (100 mL) was heated at 70° C. overnight. Thereaction mixture was filtered through CELITE filter agent, which wasrinsed with methanol and the filtrate was concentrated in vacuo to givecrude azetidin-3-ol.

Part B

Under a nitrogen atmosphere a mixture of the material from Part A,di(tert-butyl)dicarbonate (11.4 g, 52.2 mmol),N,N-dimethylpyridin-4-amine (255 mg, 2.09 mmol) andN,N-dimethylformamide (75 mL) was stirred at room temperature for 3hours. The reaction mixture was concentrated under reduced pressure andthe residue dissolved in ethyl acetate (100 mL), washed with water (2×50mL) and saturated aqueous sodium chloride (30 mL), dried over sodiumsulfate, filtered and concentrated under reduced pressure. The materialwas purified by HPFC eluting with a gradient of 0-20% ethyl acetate inhexanes to give 3.70 g of a clear oil. The oil was dissolved in methanol(200 mL), aqueous sodium hydroxide (12.6 mL of 2N) was added and thesolution was stirred at room temperature for 3 hours. The solvent waspartially removed under reduced pressure, water (20 mL) was added andthe solution was extracted with chloroform (3×100 mL). The combinedorganics were washed with saturated aqueous sodium chloride (30 mL),dried over sodium sulfate, filtered and concentrated under reducedpressure to provide 2.30 g of tert-butyl3-hydroxyazetidine-1-carboxylate as a clear oil.

Part C

Under a nitrogen atmosphere sulfur trioxide pyridine complex (6.34 g,39.8 mmol) was added portionwise to a chilled (0° C.) solution oftert-butyl 3-hydroxyazetidine-1-carboxylate (2.30 g) and triethylamine(5.55 mL, 39.8 mmol) in dimethyl sulfoxide (11.5 mL) and dichloromethane(23 mL). The solution was stirred at 0° C. for another hour, poured into70 mL of saturated aqueous ammonium chloride and then extracted withdiethyl ether (3×100 mL). The combined organics were washed with water(2×30 mL) and brine (20 mL), dried over sodium sulfate, filtered andconcentrated under reduced pressure to give tert-butyl3-oxoazetidine-1-carboxylate as a clear oil.

Part D

The material from part C was converted to tert-butyl3-(aminomethyl)-3-hydroxyazetidine-1-carboxylate according to thegeneral methods of Parts A and B of Example 4. The product was isolatedas 1.48 g of a white solid.

Part E

Tert-butyl3-[(4-amino-2-propyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]-3-hydroxyazetidine-1-carboxylatewas prepared according to the methods of Parts A through D of Example120 using tert-butyl 3-(aminomethyl)-3-hydroxyazetidine-1-carboxylate inlieu of tert-butyl 4-(aminomethyl)-4-hydroxypiperidine-1-carboxylate inpart A and using trimethylorthobutyrate in lieu oftriethylorthopropionate in Part C. The crude product was purified byHPFC eluting with a gradient of 0-25% CMA in chloroform. Triturationwith acetonitrile provided 620 mg of the pure product as an off-whitepowder, mp 134.0-135.0° C. HRMS (EI) calcd for C₂₁H₂₈N₆O₃+H, 413.2301,found 413.2319.

Exemplary Compounds Table 1

Certain exemplary compounds, including some of those described above inthe Examples, have the following Formulas (II-1, III-1, IV-1, and V-1)wherein R₂, Z, R′, and m are defined immediately below in the table. Inthis table, for each ring system, each row represents one specificcompound.

R₂ Z R′ m H Bond —OH 1 H Bond —OH 2 H Bond —OH 3 H Bond —OCH₃ 1 H Bond—OCH₃ 2 H Bond —OCH₃ 3 H Bond —NH₂ 1 H Bond —NH₂ 2 H Bond —NH₂ 3 H —CH₂——OH 1 H —CH₂— —OH 2 H —CH₂— —OH 3 H —CH₂— —OCH₃ 1 H —CH₂— —OCH₃ 2 H—CH₂— —OCH₃ 3 H —CH₂— —NH₂ 1 H —CH₂— —NH₂ 2 H —CH₂— —NH₂ 3 H —CH₂CH₂——OH 1 H —CH₂CH₂— —OH 2 H —CH₂CH₂— —OH 3 H —CH₂CH₂— —OCH₃ 1 H —CH₂CH₂——OCH₃ 2 H —CH₂CH₂— —OCH₃ 3 H —CH₂CH₂— —NH₂ 1 H —CH₂CH₂— —NH₂ 2 H—CH₂CH₂— —NH₂ 3 H —CH₂CH₂CH₂— —OH 1 H —CH₂CH₂CH₂— —OH 2 H —CH₂CH₂CH₂——OH 3 H —CH₂CH₂CH₂— —OCH₃ 1 H —CH₂CH₂CH₂— —OCH₃ 2 H —CH₂CH₂CH₂— —OCH₃ 3H —CH₂CH₂CH₂— —NH₂ 1 H —CH₂CH₂CH₂— —NH₂ 2 H —CH₂CH₂CH₂— —NH₂ 3 H—CH₂—O—CH₂— —OH 1 H —CH₂—O—CH₂— —OH 2 H —CH₂—O—CH₂— —OH 3 H —CH₂—O—CH₂——OCH₃ 1 H —CH₂—O—CH₂— —OCH₃ 2 H —CH₂—O—CH₂— —OCH₃ 3 H —CH₂—O—CH₂— —NH₂ 1H —CH₂—O—CH₂— —NH₂ 2 H —CH₂—O—CH₂— —NH₂ 3 methyl Bond —OH 1 methyl Bond—OH 2 methyl Bond —OH 3 methyl Bond —OCH₃ 1 methyl Bond —OCH₃ 2 methylBond —OCH₃ 3 methyl Bond —NH₂ 1 methyl Bond —NH₂ 2 methyl Bond —NH₂ 3methyl —CH₂— —OH 1 methyl —CH₂— —OH 2 methyl —CH₂— —OH 3 methyl —CH₂——OCH₃ 1 methyl —CH₂— —OCH₃ 2 methyl —CH₂— —OCH₃ 3 methyl —CH₂— —NH₂ 1methyl —CH₂— —NH₂ 2 methyl —CH₂— —NH₂ 3 methyl —CH₂CH₂— —OH 1 methyl—CH₂CH₂— —OH 2 methyl —CH₂CH₂— —OH 3 methyl —CH₂CH₂— —OCH₃ 1 methyl—CH₂CH₂— —OCH₃ 2 methyl —CH₂CH₂— —OCH₃ 3 methyl —CH₂CH₂— —NH₂ 1 methyl—CH₂CH₂— —NH₂ 2 methyl —CH₂CH₂— —NH₂ 3 methyl —CH₂CH₂CH₂— —OH 1 methyl—CH₂CH₂CH₂— —OH 2 methyl —CH₂CH₂CH₂— —OH 3 methyl —CH₂CH₂CH₂— —OCH₃ 1methyl —CH₂CH₂CH₂— —OCH₃ 2 methyl —CH₂CH₂CH₂— —OCH₃ 3 methyl —CH₂CH₂CH₂——NH₂ 1 methyl —CH₂CH₂CH₂— —NH₂ 2 methyl —CH₂CH₂CH₂— —NH₂ 3 methyl—CH₂—O—CH₂— —OH 1 methyl —CH₂—O—CH₂— —OH 2 methyl —CH₂—O—CH₂— —OH 3methyl —CH₂—O—CH₂— —OCH₃ 1 methyl —CH₂—O—CH₂— —OCH₃ 2 methyl —CH₂—O—CH₂——OCH₃ 3 methyl —CH₂—O—CH₂— —NH₂ 1 methyl —CH₂—O—CH₂— —NH₂ 2 methyl—CH₂—O—CH₂— —NH₂ 3 ethyl Bond —OH 1 ethyl Bond —OH 2 ethyl Bond —OH 3ethyl Bond —OCH₃ 1 ethyl Bond —OCH₃ 2 ethyl Bond —OCH₃ 3 ethyl Bond —NH₂1 ethyl Bond —NH₂ 2 ethyl Bond —NH₂ 3 ethyl —CH₂— —OH 1 ethyl —CH₂— —OH2 ethyl —CH₂— —OH 3 ethyl —CH₂— —OCH₃ 1 ethyl —CH₂— —OCH₃ 2 ethyl —CH₂——OCH₃ 3 ethyl —CH₂— —NH₂ 1 ethyl —CH₂— —NH₂ 2 ethyl —CH₂— —NH₂ 3 ethyl—CH₂CH₂— —OH 1 ethyl —CH₂CH₂— —OH 2 ethyl —CH₂CH₂— —OH 3 ethyl —CH₂CH₂——OCH₃ 1 ethyl —CH₂CH₂— —OCH₃ 2 ethyl —CH₂CH₂— —OCH₃ 3 ethyl —CH₂CH₂——NH₂ 1 ethyl —CH₂CH₂— —NH₂ 2 ethyl —CH₂CH₂— —NH₂ 3 ethyl —CH₂CH₂CH₂— —OH1 ethyl —CH₂CH₂CH₂— —OH 2 ethyl —CH₂CH₂CH₂— —OH 3 ethyl —CH₂CH₂CH₂——OCH₃ 1 ethyl —CH₂CH₂CH₂— —OCH₃ 2 ethyl —CH₂CH₂CH₂— —OCH₃ 3 ethyl—CH₂CH₂CH₂— —NH₂ 1 ethyl —CH₂CH₂CH₂— —NH₂ 2 ethyl —CH₂CH₂CH₂— —NH₂ 3ethyl —CH₂—O—CH₂— —OH 1 ethyl —CH₂—O—CH₂— —OH 2 ethyl —CH₂—O—CH₂— —OH 3ethyl —CH₂—O—CH₂— —OCH₃ 1 ethyl —CH₂—O—CH₂— —OCH₃ 2 ethyl —CH₂—O—CH₂——OCH₃ 3 ethyl —CH₂—O—CH₂— —NH₂ 1 ethyl —CH₂—O—CH₂— —NH₂ 2 ethyl—CH₂—O—CH₂— —NH₂ 3 n-propyl Bond —OH 1 n-propyl Bond —OH 2 n-propyl Bond—OH 3 n-propyl Bond —OCH₃ 1 n-propyl Bond —OCH₃ 2 n-propyl Bond —OCH₃ 3n-propyl Bond —NH₂ 1 n-propyl Bond —NH₂ 2 n-propyl Bond —NH₂ 3 n-propyl—CH₂— —OH 1 n-propyl —CH₂— —OH 2 n-propyl —CH₂— —OH 3 n-propyl —CH₂——OCH₃ 1 n-propyl —CH₂— —OCH₃ 2 n-propyl —CH₂— —OCH₃ 3 n-propyl —CH₂——NH₂ 1 n-propyl —CH₂— —NH₂ 2 n-propyl —CH₂— —NH₂ 3 n-propyl —CH₂CH₂— —OH1 n-propyl —CH₂CH₂— —OH 2 n-propyl —CH₂CH₂— —OH 3 n-propyl —CH₂CH₂——OCH₃ 1 n-propyl —CH₂CH₂— —OCH₃ 2 n-propyl —CH₂CH₂— —OCH₃ 3 n-propyl—CH₂CH₂— —NH₂ 1 n-propyl —CH₂CH₂— —NH₂ 2 n-propyl —CH₂CH₂— —NH₂ 3n-propyl —CH₂CH₂CH₂— —OH 1 n-propyl —CH₂CH₂CH₂— —OH 2 n-propyl—CH₂CH₂CH₂— —OH 3 n-propyl —CH₂CH₂CH₂— —OCH₃ 1 n-propyl —CH₂CH₂CH₂——OCH₃ 2 n-propyl —CH₂CH₂CH₂— —OCH₃ 3 n-propyl —CH₂CH₂CH₂— —NH₂ 1n-propyl —CH₂CH₂CH₂— —NH₂ 2 n-propyl —CH₂CH₂CH₂— —NH₂ 3 n-propyl—CH₂—O—CH₂— —OH 1 n-propyl —CH₂—O—CH₂— —OH 2 n-propyl —CH₂—O—CH₂— —OH 3n-propyl —CH₂—O—CH₂— —OCH₃ 1 n-propyl —CH₂—O—CH₂— —OCH₃ 2 n-propyl—CH₂—O—CH₂— —OCH₃ 3 n-propyl —CH₂—O—CH₂— —NH₂ 1 n-propyl —CH₂—O—CH₂——NH₂ 2 n-propyl —CH₂—O—CH₂— —NH₂ 3 n-butyl Bond —OH 1 n-butyl Bond —OH 2n-butyl Bond —OH 3 n-butyl Bond —OCH₃ 1 n-butyl Bond —OCH₃ 2 n-butylBond —OCH₃ 3 n-butyl Bond —NH₂ 1 n-butyl Bond —NH₂ 2 n-butyl Bond —NH₂ 3n-butyl —CH₂— —OH 1 n-butyl —CH₂— —OH 2 n-butyl —CH₂— —OH 3 n-butyl—CH₂— —OCH₃ 1 n-butyl —CH₂— —OCH₃ 2 n-butyl —CH₂— —OCH₃ 3 n-butyl —CH₂——NH₂ 1 n-butyl —CH₂— —NH₂ 2 n-butyl —CH₂— —NH₂ 3 n-butyl —CH₂CH₂— —OH 1n-butyl —CH₂CH₂— —OH 2 n-butyl —CH₂CH₂— —OH 3 n-butyl —CH₂CH₂— —OCH₃ 1n-butyl —CH₂CH₂— —OCH₃ 2 n-butyl —CH₂CH₂— —OCH₃ 3 n-butyl —CH₂CH₂— —NH₂1 n-butyl —CH₂CH₂— —NH₂ 2 n-butyl —CH₂CH₂— —NH₂ 3 n-butyl —CH₂CH₂CH₂——OH 1 n-butyl —CH₂CH₂CH₂— —OH 2 n-butyl —CH₂CH₂CH₂— —OH 3 n-butyl—CH₂CH₂CH₂— —OCH₃ 1 n-butyl —CH₂CH₂CH₂— —OCH₃ 2 n-butyl —CH₂CH₂CH₂——OCH₃ 3 n-butyl —CH₂CH₂CH₂— —NH₂ 1 n-butyl —CH₂CH₂CH₂— —NH₂ 2 n-butyl—CH₂CH₂CH₂— —NH₂ 3 n-butyl —CH₂—O—CH₂— —OH 1 n-butyl —CH₂—O—CH₂— —OH 2n-butyl —CH₂—O—CH₂— —OH 3 n-butyl —CH₂—O—CH₂— —OCH₃ 1 n-butyl—CH₂—O—CH₂— —OCH₃ 2 n-butyl —CH₂—O—CH₂— —OCH₃ 3 n-butyl —CH₂—O—CH₂— —NH₂1 n-butyl —CH₂—O—CH₂— —NH₂ 2 n-butyl —CH₂—O—CH₂— —NH₂ 3 ethoxymethylBond —OH 1 ethoxymethyl Bond —OH 2 ethoxymethyl Bond —OH 3 ethoxymethylBond —OCH₃ 1 ethoxymethyl Bond —OCH₃ 2 ethoxymethyl Bond —OCH₃ 3ethoxymethyl Bond —NH₂ 1 ethoxymethyl Bond —NH₂ 2 ethoxymethyl Bond —NH₂3 ethoxymethyl —CH₂— —OH 1 ethoxymethyl —CH₂— —OH 2 ethoxymethyl —CH₂——OH 3 ethoxymethyl —CH₂— —OCH₃ 1 ethoxymethyl —CH₂— —OCH₃ 2 ethoxymethyl—CH₂— —OCH₃ 3 ethoxymethyl —CH₂— —NH₂ 1 ethoxymethyl —CH₂— —NH₂ 2ethoxymethyl —CH₂— —NH₂ 3 ethoxymethyl —CH₂CH₂— —OH 1 ethoxymethyl—CH₂CH₂— —OH 2 ethoxymethyl —CH₂CH₂— —OH 3 ethoxymethyl —CH₂CH₂— —OCH₃ 1ethoxymethyl —CH₂CH₂— —OCH₃ 2 ethoxymethyl —CH₂CH₂— —OCH₃ 3 ethoxymethyl—CH₂CH₂— —NH₂ 1 ethoxymethyl —CH₂CH₂— —NH₂ 2 ethoxymethyl —CH₂CH₂— —NH₂3 ethoxymethyl —CH₂CH₂CH₂— —OH 1 ethoxymethyl —CH₂CH₂CH₂— —OH 2ethoxymethyl —CH₂CH₂CH₂— —OH 3 ethoxymethyl —CH₂CH₂CH₂— —OCH₃ 1ethoxymethyl —CH₂CH₂CH₂— —OCH₃ 2 ethoxymethyl —CH₂CH₂CH₂— —OCH₃ 3ethoxymethyl —CH₂CH₂CH₂— —NH₂ 1 ethoxymethyl —CH₂CH₂CH₂— —NH₂ 2ethoxymethyl —CH₂CH₂CH₂— —NH₂ 3 ethoxymethyl —CH₂—O—CH₂— —OH 1ethoxymethyl —CH₂—O—CH₂— —OH 2 ethoxymethyl —CH₂—O—CH₂— —OH 3ethoxymethyl —CH₂—O—CH₂— —OCH₃ 1 ethoxymethyl —CH₂—O—CH₂— —OCH₃ 2ethoxymethyl —CH₂—O—CH₂— —OCH₃ 3 ethoxymethyl —CH₂—O—CH₂— —NH₂ 1ethoxymethyl —CH₂—O—CH₂— —NH₂ 2 ethoxymethyl —CH₂—O—CH₂— —NH₂ 32-methoxyethyl Bond —OH 1 2-methoxyethyl Bond —OH 2 2-methoxyethyl Bond—OH 3 2-methoxyethyl Bond —OCH₃ 1 2-methoxyethyl Bond —OCH₃ 22-methoxyethyl Bond —OCH₃ 3 2-methoxyethyl Bond —NH₂ 1 2-methoxyethylBond —NH₂ 2 2-methoxyethyl Bond —NH₂ 3 2-methoxyethyl —CH₂— —OH 12-methoxyethyl —CH₂— —OH 2 2-methoxyethyl —CH₂— —OH 3 2-methoxyethyl—CH₂— —OCH₃ 1 2-methoxyethyl —CH₂— —OCH₃ 2 2-methoxyethyl —CH₂— —OCH₃ 32-methoxyethyl —CH₂— —NH₂ 1 2-methoxyethyl —CH₂— —NH₂ 2 2-methoxyethyl—CH₂— —NH₂ 3 2-methoxyethyl —CH₂CH₂— —OH 1 2-methoxyethyl —CH₂CH₂— —OH 22-methoxyethyl —CH₂CH₂— —OH 3 2-methoxyethyl —CH₂CH₂— —OCH₃ 12-methoxyethyl —CH₂CH₂— —OCH₃ 2 2-methoxyethyl —CH₂CH₂— —OCH₃ 32-methoxyethyl —CH₂CH₂— —NH₂ 1 2-methoxyethyl —CH₂CH₂— —NH₂ 22-methoxyethyl —CH₂CH₂— —NH₂ 3 2-methoxyethyl —CH₂CH₂CH₂— —OH 12-methoxyethyl —CH₂CH₂CH₂— —OH 2 2-methoxyethyl —CH₂CH₂CH₂— —OH 32-methoxyethyl —CH₂CH₂CH₂— —OCH₃ 1 2-methoxyethyl —CH₂CH₂CH₂— —OCH₃ 22-methoxyethyl —CH₂CH₂CH₂— —OCH₃ 3 2-methoxyethyl —CH₂CH₂CH₂— —NH₂ 12-methoxyethyl —CH₂CH₂CH₂— —NH₂ 2 2-methoxyethyl —CH₂CH₂CH₂— —NH₂ 32-methoxyethyl —CH₂—O—CH₂— —OH 1 2-methoxyethyl —CH₂—O—CH₂— —OH 22-methoxyethyl —CH₂—O—CH₂— —OH 3 2-methoxyethyl —CH₂—O—CH₂— —OCH₃ 12-methoxyethyl —CH₂—O—CH₂— —OCH₃ 2 2-methoxyethyl —CH₂—O—CH₂— —OCH₃ 32-methoxyethyl —CH₂—O—CH₂— —NH₂ 1 2-methoxyethyl —CH₂—O—CH₂— —NH₂ 22-methoxyethyl —CH₂—O—CH₂— —NH₂ 3Exemplary Compounds Table 2

Certain exemplary compounds, including some of those described above inthe Examples, have the following Formulas (II-2, III-2, IV-2, and V-2)wherein R₂, Q, R′, R₄, and m are defined immediately below in the table.In this table, for each ring system, each row represents one specificcompound.

R₂ Q R₄ R′ m H Bond Methyl —OH 1 H Bond Methyl —OH 2 H Bond Methyl —OH 3H Bond Methyl —OCH₃ 1 H Bond methyl —OCH₃ 2 H Bond methyl —OCH₃ 3 H Bondethyl —OH 1 H Bond ethyl —OH 2 H Bond ethyl —OH 3 H Bond ethyl —OCH₃ 1 HBond ethyl —OCH₃ 2 H Bond ethyl —OCH₃ 3 H Bond isopropyl —OH 1 H Bondisopropyl —OH 2 H Bond isopropyl —OH 3 H Bond isopropyl —OCH₃ 1 H Bondisopropyl —OCH₃ 2 H Bond isopropyl —OCH₃ 3 H Bond phenyl —OH 1 H Bondphenyl —OH 2 H Bond phenyl —OH 3 H Bond phenyl —OCH₃ 1 H Bond phenyl—OCH₃ 2 H Bond phenyl —OCH₃ 3 H —C(O)— methyl —OH 1 H —C(O)— methyl —OH2 H —C(O)— methyl —OH 3 H —C(O)— methyl —OCH₃ 1 H —C(O)— methyl —OCH₃ 2H —C(O)— methyl —OCH₃ 3 H —C(O)— ethyl —OH 1 H —C(O)— ethyl —OH 2 H—C(O)— ethyl —OH 3 H —C(O)— ethyl —OCH₃ 1 H —C(O)— ethyl —OCH₃ 2 H—C(O)— ethyl —OCH₃ 3 H —C(O)— isopropyl —OH 1 H —C(O)— isopropyl —OH 2 H—C(O)— isopropyl —OH 3 H —C(O)— isopropyl —OCH₃ 1 H —C(O)— isopropyl—OCH₃ 2 H —C(O)— isopropyl —OCH₃ 3 H —C(O)— phenyl —OH 1 H —C(O)— phenyl—OH 2 H —C(O)— phenyl —OH 3 H —C(O)— phenyl —OCH₃ 1 H —C(O)— phenyl—OCH₃ 2 H —C(O)— phenyl —OCH₃ 3 H —S(O)₂— methyl —OH 1 H —S(O)₂— methyl—OH 2 H —S(O)₂— methyl —OH 3 H —S(O)₂— methyl —OCH₃ 1 H —S(O)₂— methyl—OCH₃ 2 H —S(O)₂— methyl —OCH₃ 3 H —S(O)₂— ethyl —OH 1 H —S(O)₂— ethyl—OH 2 H —S(O)₂— ethyl —OH 3 H —S(O)₂— ethyl —OCH₃ 1 H —S(O)₂— ethyl—OCH₃ 2 H —S(O)₂— ethyl —OCH₃ 3 H —S(O)₂— isopropyl —OH 1 H —S(O)₂—isopropyl —OH 2 H —S(O)₂— isopropyl —OH 3 H —S(O)₂— isopropyl —OCH₃ 1 H—S(O)₂— isopropyl —OCH₃ 2 H —S(O)₂— isopropyl —OCH₃ 3 H —S(O)₂— phenyl—OH 1 H —S(O)₂— phenyl —OH 2 H —S(O)₂— phenyl —OH 3 H —S(O)₂— phenyl—OCH₃ 1 H —S(O)₂— phenyl —OCH₃ 2 H —S(O)₂— phenyl —OCH₃ 3 H —C(O)—NH—methyl —OH 1 H —C(O)—NH— methyl —OH 2 H —C(O)—NH— methyl —OH 3 H—C(O)—NH— methyl —OCH₃ 1 H —C(O)—NH— methyl —OCH₃ 2 H —C(O)—NH— methyl—OCH₃ 3 H —C(O)—NH— ethyl —OH 1 H —C(O)—NH— ethyl —OH 2 H —C(O)—NH—ethyl —OH 3 H —C(O)—NH— ethyl —OCH₃ 1 H —C(O)—NH— ethyl —OCH₃ 2 H—C(O)—NH— ethyl —OCH₃ 3 H —C(O)—NH— isopropyl —OH 1 H —C(O)—NH—isopropyl —OH 2 H —C(O)—NH— isopropyl —OH 3 H —C(O)—NH— isopropyl —OCH₃1 H —C(O)—NH— isopropyl —OCH₃ 2 H —C(O)—NH— isopropyl —OCH₃ 3 H—C(O)—NH— phenyl —OH 1 H —C(O)—NH— phenyl —OH 2 H —C(O)—NH— phenyl —OH 3H —C(O)—NH— phenyl —OCH₃ 1 H —C(O)—NH— phenyl —OCH₃ 2 H —C(O)—NH— phenyl—OCH₃ 3 methyl Bond methyl —OH 1 methyl Bond methyl —OH 2 methyl Bondmethyl —OH 3 methyl Bond methyl —OCH₃ 1 methyl Bond methyl —OCH₃ 2methyl Bond methyl —OCH₃ 3 methyl Bond ethyl —OH 1 methyl Bond ethyl —OH2 methyl Bond ethyl —OH 3 methyl Bond ethyl —OCH₃ 1 methyl Bond ethyl—OCH₃ 2 methyl Bond ethyl —OCH₃ 3 methyl Bond isopropyl —OH 1 methylBond isopropyl —OH 2 methyl Bond isopropyl —OH 3 methyl Bond isopropyl—OCH₃ 1 methyl Bond isopropyl —OCH₃ 2 methyl Bond isopropyl —OCH₃ 3methyl Bond phenyl —OH 1 methyl Bond phenyl —OH 2 methyl Bond phenyl —OH3 methyl Bond phenyl —OCH₃ 1 methyl Bond phenyl —OCH₃ 2 methyl Bondphenyl —OCH₃ 3 methyl —C(O)— methyl —OH 1 methyl —C(O)— methyl —OH 2methyl —C(O)— methyl —OH 3 methyl —C(O)— methyl —OCH₃ 1 methyl —C(O)—methyl —OCH₃ 2 methyl —C(O)— methyl —OCH₃ 3 methyl —C(O)— ethyl —OH 1methyl —C(O)— ethyl —OH 2 methyl —C(O)— ethyl —OH 3 methyl —C(O)— ethyl—OCH₃ 1 methyl —C(O)— ethyl —OCH₃ 2 methyl —C(O)— ethyl —OCH₃ 3 methyl—C(O)— isopropyl —OH 1 methyl —C(O)— isopropyl —OH 2 methyl —C(O)—isopropyl —OH 3 methyl —C(O)— isopropyl —OCH₃ 1 methyl —C(O)— isopropyl—OCH₃ 2 methyl —C(O)— isopropyl —OCH₃ 3 methyl —C(O)— phenyl —OH 1methyl —C(O)— phenyl —OH 2 methyl —C(O)— phenyl —OH 3 methyl —C(O)—phenyl —OCH₃ 1 methyl —C(O)— phenyl —OCH₃ 2 methyl —C(O)— phenyl —OCH₃ 3methyl —S(O)₂— methyl —OH 1 methyl —S(O)₂— methyl —OH 2 methyl —S(O)₂—methyl —OH 3 methyl —S(O)₂— methyl —OCH₃ 1 methyl —S(O)₂— methyl —OCH₃ 2methyl —S(O)₂— methyl —OCH₃ 3 methyl —S(O)₂— ethyl —OH 1 methyl —S(O)₂—ethyl —OH 2 methyl —S(O)₂— ethyl —OH 3 methyl —S(O)₂— ethyl —OCH₃ 1methyl —S(O)₂— ethyl —OCH₃ 2 methyl —S(O)₂— ethyl —OCH₃ 3 methyl —S(O)₂—isopropyl —OH 1 methyl —S(O)₂— isopropyl —OH 2 methyl —S(O)₂— isopropyl—OH 3 methyl —S(O)₂— isopropyl —OCH₃ 1 methyl —S(O)₂— isopropyl —OCH₃ 2methyl —S(O)₂— isopropyl —OCH₃ 3 methyl —S(O)₂— phenyl —OH 1 methyl—S(O)₂— phenyl —OH 2 methyl —S(O)₂— phenyl —OH 3 methyl —S(O)₂— phenyl—OCH₃ 1 methyl —S(O)₂— phenyl —OCH₃ 2 methyl —S(O)₂— phenyl —OCH₃ 3methyl —C(O)—NH— methyl —OH 1 methyl —C(O)—NH— methyl —OH 2 methyl—C(O)—NH— methyl —OH 3 methyl —C(O)—NH— methyl —OCH₃ 1 methyl —C(O)—NH—methyl —OCH₃ 2 methyl —C(O)—NH— methyl —OCH₃ 3 methyl —C(O)—NH— ethyl—OH 1 methyl —C(O)—NH— ethyl —OH 2 methyl —C(O)—NH— ethyl —OH 3 methyl—C(O)—NH— ethyl —OCH₃ 1 methyl —C(O)—NH— ethyl —OCH₃ 2 methyl —C(O)—NH—ethyl —OCH₃ 3 methyl —C(O)—NH— isopropyl —OH 1 methyl —C(O)—NH—isopropyl —OH 2 methyl —C(O)—NH— isopropyl —OH 3 methyl —C(O)—NH—isopropyl —OCH₃ 1 methyl —C(O)—NH— isopropyl —OCH₃ 2 methyl —C(O)—NH—isopropyl —OCH₃ 3 methyl —C(O)—NH— phenyl —OH 1 methyl —C(O)—NH— phenyl—OH 2 methyl —C(O)—NH— phenyl —OH 3 methyl —C(O)—NH— phenyl —OCH₃ 1methyl —C(O)—NH— phenyl —OCH₃ 2 methyl —C(O)—NH— phenyl —OCH₃ 3 ethylBond methyl —OH 1 ethyl Bond methyl —OH 2 ethyl Bond methyl —OH 3 ethylBond methyl —OCH₃ 1 ethyl Bond methyl —OCH₃ 2 ethyl Bond methyl —OCH₃ 3ethyl Bond ethyl —OH 1 ethyl Bond ethyl —OH 2 ethyl Bond ethyl —OH 3ethyl Bond ethyl —OCH₃ 1 ethyl Bond ethyl —OCH₃ 2 ethyl Bond ethyl —OCH₃3 ethyl Bond isopropyl —OH 1 ethyl Bond isopropyl —OH 2 ethyl Bondisopropyl —OH 3 ethyl Bond isopropyl —OCH₃ 1 ethyl Bond isopropyl —OCH₃2 ethyl Bond isopropyl —OCH₃ 3 ethyl Bond phenyl —OH 1 ethyl Bond phenyl—OH 2 ethyl Bond phenyl —OH 3 ethyl Bond phenyl —OCH₃ 1 ethyl Bondphenyl —OCH₃ 2 ethyl Bond phenyl —OCH₃ 3 ethyl —C(O)— methyl —OH 1 ethyl—C(O)— methyl —OH 2 ethyl —C(O)— methyl —OH 3 ethyl —C(O)— methyl —OCH₃1 ethyl —C(O)— methyl —OCH₃ 2 ethyl —C(O)— methyl —OCH₃ 3 ethyl —C(O)—ethyl —OH 1 ethyl —C(O)— ethyl —OH 2 ethyl —C(O)— ethyl —OH 3 ethyl—C(O)— ethyl —OCH₃ 1 ethyl —C(O)— ethyl —OCH₃ 2 ethyl —C(O)— ethyl —OCH₃3 ethyl —C(O)— isopropyl —OH 1 ethyl —C(O)— isopropyl —OH 2 ethyl —C(O)—isopropyl —OH 3 ethyl —C(O)— isopropyl —OCH₃ 1 ethyl —C(O)— isopropyl—OCH₃ 2 ethyl —C(O)— isopropyl —OCH₃ 3 ethyl —C(O)— phenyl —OH 1 ethyl—C(O)— phenyl —OH 2 ethyl —C(O)— phenyl —OH 3 ethyl —C(O)— phenyl —OCH₃1 ethyl —C(O)— phenyl —OCH₃ 2 ethyl —C(O)— phenyl —OCH₃ 3 ethyl —S(O)₂—methyl —OH 1 ethyl —S(O)₂— methyl —OH 2 ethyl —S(O)₂— methyl —OH 3 ethyl—S(O)₂— methyl —OCH₃ 1 ethyl —S(O)₂— methyl —OCH₃ 2 ethyl —S(O)₂— methyl—OCH₃ 3 ethyl —S(O)₂— ethyl —OH 1 ethyl —S(O)₂— ethyl —OH 2 ethyl—S(O)₂— ethyl —OH 3 ethyl —S(O)₂— ethyl —OCH₃ 1 ethyl —S(O)₂— ethyl—OCH₃ 2 ethyl —S(O)₂— ethyl —OCH₃ 3 ethyl —S(O)₂— isopropyl —OH 1 ethyl—S(O)₂— isopropyl —OH 2 ethyl —S(O)₂— isopropyl —OH 3 ethyl —S(O)₂—isopropyl —OCH₃ 1 ethyl —S(O)₂— isopropyl —OCH₃ 2 ethyl —S(O)₂—isopropyl —OCH₃ 3 ethyl —S(O)₂— phenyl —OH 1 ethyl —S(O)₂— phenyl —OH 2ethyl —S(O)₂— phenyl —OH 3 ethyl —S(O)₂— phenyl —OCH₃ 1 ethyl —S(O)₂—phenyl —OCH₃ 2 ethyl —S(O)₂— phenyl —OCH₃ 3 ethyl —C(O)—NH— methyl —OH 1ethyl —C(O)—NH— methyl —OH 2 ethyl —C(O)—NH— methyl —OH 3 ethyl—C(O)—NH— methyl —OCH₃ 1 ethyl —C(O)—NH— methyl —OCH₃ 2 ethyl —C(O)—NH—methyl —OCH₃ 3 ethyl —C(O)—NH— ethyl —OH 1 ethyl —C(O)—NH— ethyl —OH 2ethyl —C(O)—NH— ethyl —OH 3 ethyl —C(O)—NH— ethyl —OCH₃ 1 ethyl—C(O)—NH— ethyl —OCH₃ 2 ethyl —C(O)—NH— ethyl —OCH₃ 3 ethyl —C(O)—NH—isopropyl —OH 1 ethyl —C(O)—NH— isopropyl —OH 2 ethyl —C(O)—NH—isopropyl —OH 3 ethyl —C(O)—NH— isopropyl —OCH₃ 1 ethyl —C(O)—NH—isopropyl —OCH₃ 2 ethyl —C(O)—NH— isopropyl —OCH₃ 3 ethyl —C(O)—NH—phenyl —OH 1 ethyl —C(O)—NH— phenyl —OH 2 ethyl —C(O)—NH— phenyl —OH 3ethyl —C(O)—NH— phenyl —OCH₃ 1 ethyl —C(O)—NH— phenyl —OCH₃ 2 ethyl—C(O)—NH— phenyl —OCH₃ 3 n-propyl Bond methyl —OH 1 n-propyl Bond methyl—OH 2 n-propyl Bond methyl —OH 3 n-propyl Bond methyl —OCH₃ 1 n-propylBond methyl —OCH₃ 2 n-propyl Bond methyl —OCH₃ 3 n-propyl Bond ethyl —OH1 n-propyl Bond ethyl —OH 2 n-propyl Bond ethyl —OH 3 n-propyl Bondethyl —OCH₃ 1 n-propyl Bond ethyl —OCH₃ 2 n-propyl Bond ethyl —OCH₃ 3n-propyl Bond isopropyl —OH 1 n-propyl Bond isopropyl —OH 2 n-propylBond isopropyl —OH 3 n-propyl Bond isopropyl —OCH₃ 1 n-propyl Bondisopropyl —OCH₃ 2 n-propyl Bond isopropyl —OCH₃ 3 n-propyl Bond phenyl—OH 1 n-propyl Bond phenyl —OH 2 n-propyl Bond phenyl —OH 3 n-propylBond phenyl —OCH₃ 1 n-propyl Bond phenyl —OCH₃ 2 n-propyl Bond phenyl—OCH₃ 3 n-propyl —C(O)— methyl —OH 1 n-propyl —C(O)— methyl —OH 2n-propyl —C(O)— methyl —OH 3 n-propyl —C(O)— methyl —OCH₃ 1 n-propyl—C(O)— methyl —OCH₃ 2 n-propyl —C(O)— methyl —OCH₃ 3 n-propyl —C(O)—ethyl —OH 1 n-propyl —C(O)— ethyl —OH 2 n-propyl —C(O)— ethyl —OH 3n-propyl —C(O)— ethyl —OCH₃ 1 n-propyl —C(O)— ethyl —OCH₃ 2 n-propyl—C(O)— ethyl —OCH₃ 3 n-propyl —C(O)— isopropyl —OH 1 n-propyl —C(O)—isopropyl —OH 2 n-propyl —C(O)— isopropyl —OH 3 n-propyl —C(O)—isopropyl —OCH₃ 1 n-propyl —C(O)— isopropyl —OCH₃ 2 n-propyl —C(O)—isopropyl —OCH₃ 3 n-propyl —C(O)— phenyl —OH 1 n-propyl —C(O)— phenyl—OH 2 n-propyl —C(O)— phenyl —OH 3 n-propyl —C(O)— phenyl —OCH₃ 1n-propyl —C(O)— phenyl —OCH₃ 2 n-propyl —C(O)— phenyl —OCH₃ 3 n-propyl—S(O)₂— methyl —OH 1 n-propyl —S(O)₂— methyl —OH 2 n-propyl —S(O)₂—methyl —OH 3 n-propyl —S(O)₂— methyl —OCH₃ 1 n-propyl —S(O)₂— methyl—OCH₃ 2 n-propyl —S(O)₂— methyl —OCH₃ 3 n-propyl —S(O)₂— ethyl —OH 1n-propyl —S(O)₂— ethyl —OH 2 n-propyl —S(O)₂— ethyl —OH 3 n-propyl—S(O)₂— ethyl —OCH₃ 1 n-propyl —S(O)₂— ethyl —OCH₃ 2 n-propyl —S(O)₂—ethyl —OCH₃ 3 n-propyl —S(O)₂— isopropyl —OH 1 n-propyl —S(O)₂—isopropyl —OH 2 n-propyl —S(O)₂— isopropyl —OH 3 n-propyl —S(O)₂—isopropyl —OCH₃ 1 n-propyl —S(O)₂— isopropyl —OCH₃ 2 n-propyl —S(O)₂—isopropyl —OCH₃ 3 n-propyl —S(O)₂— phenyl —OH 1 n-propyl —S(O)₂— phenyl—OH 2 n-propyl —S(O)₂— phenyl —OH 3 n-propyl —S(O)₂— phenyl —OCH₃ 1n-propyl —S(O)₂— phenyl —OCH₃ 2 n-propyl —S(O)₂— phenyl —OCH₃ 3 n-propyl—C(O)—NH— methyl —OH 1 n-propyl —C(O)—NH— methyl —OH 2 n-propyl—C(O)—NH— methyl —OH 3 n-propyl —C(O)—NH— methyl —OCH₃ 1 n-propyl—C(O)—NH— methyl —OCH₃ 2 n-propyl —C(O)—NH— methyl —OCH₃ 3 n-propyl—C(O)—NH— ethyl —OH 1 n-propyl —C(O)—NH— ethyl —OH 2 n-propyl —C(O)—NH—ethyl —OH 3 n-propyl —C(O)—NH— ethyl —OCH₃ 1 n-propyl —C(O)—NH— ethyl—OCH₃ 2 n-propyl —C(O)—NH— ethyl —OCH₃ 3 n-propyl —C(O)—NH— isopropyl—OH 1 n-propyl —C(O)—NH— isopropyl —OH 2 n-propyl —C(O)—NH— isopropyl—OH 3 n-propyl —C(O)—NH— isopropyl —OCH₃ 1 n-propyl —C(O)—NH— isopropyl—OCH₃ 2 n-propyl —C(O)—NH— isopropyl —OCH₃ 3 n-propyl —C(O)—NH— phenyl—OH 1 n-propyl —C(O)—NH— phenyl —OH 2 n-propyl —C(O)—NH— phenyl —OH 3n-propyl —C(O)—NH— phenyl —OCH₃ 1 n-propyl —C(O)—NH— phenyl —OCH₃ 2n-propyl —C(O)—NH— phenyl —OCH₃ 3 n-butyl Bond methyl —OH 1 n-butyl Bondmethyl —OH 2 n-butyl Bond methyl —OH 3 n-butyl Bond methyl —OCH₃ 1n-butyl Bond methyl —OCH₃ 2 n-butyl Bond methyl —OCH₃ 3 n-butyl Bondethyl —OH 1 n-butyl Bond ethyl —OH 2 n-butyl Bond ethyl —OH 3 n-butylBond ethyl —OCH₃ 1 n-butyl Bond ethyl —OCH₃ 2 n-butyl Bond ethyl —OCH₃ 3n-butyl Bond isopropyl —OH 1 n-butyl Bond isopropyl —OH 2 n-butyl Bondisopropyl —OH 3 n-butyl Bond isopropyl —OCH₃ 1 n-butyl Bond isopropyl—OCH₃ 2 n-butyl Bond isopropyl —OCH₃ 3 n-butyl Bond phenyl —OH 1 n-butylBond phenyl —OH 2 n-butyl Bond phenyl —OH 3 n-butyl Bond phenyl —OCH₃ 1n-butyl Bond phenyl —OCH₃ 2 n-butyl Bond phenyl —OCH₃ 3 n-butyl —C(O)—methyl —OH 1 n-butyl —C(O)— methyl —OH 2 n-butyl —C(O)— methyl —OH 3n-butyl —C(O)— methyl —OCH₃ 1 n-butyl —C(O)— methyl —OCH₃ 2 n-butyl—C(O)— methyl —OCH₃ 3 n-butyl —C(O)— ethyl —OH 1 n-butyl —C(O)— ethyl—OH 2 n-butyl —C(O)— ethyl —OH 3 n-butyl —C(O)— ethyl —OCH₃ 1 n-butyl—C(O)— ethyl —OCH₃ 2 n-butyl —C(O)— ethyl —OCH₃ 3 n-butyl —C(O)—isopropyl —OH 1 n-butyl —C(O)— isopropyl —OH 2 n-butyl —C(O)— isopropyl—OH 3 n-butyl —C(O)— isopropyl —OCH₃ 1 n-butyl —C(O)— isopropyl —OCH₃ 2n-butyl —C(O)— isopropyl —OCH₃ 3 n-butyl —C(O)— phenyl —OH 1 n-butyl—C(O)— phenyl —OH 2 n-butyl —C(O)— phenyl —OH 3 n-butyl —C(O)— phenyl—OCH₃ 1 n-butyl —C(O)— phenyl —OCH₃ 2 n-butyl —C(O)— phenyl —OCH₃ 3n-butyl —S(O)₂— methyl —OH 1 n-butyl —S(O)₂— methyl —OH 2 n-butyl—S(O)₂— methyl —OH 3 n-butyl —S(O)₂— methyl —OCH₃ 1 n-butyl —S(O)₂—methyl —OCH₃ 2 n-butyl —S(O)₂— methyl —OCH₃ 3 n-butyl —S(O)₂— ethyl —OH1 n-butyl —S(O)₂— ethyl —OH 2 n-butyl —S(O)₂— ethyl —OH 3 n-butyl—S(O)₂— ethyl —OCH₃ 1 n-butyl —S(O)₂— ethyl —OCH₃ 2 n-butyl —S(O)₂—ethyl —OCH₃ 3 n-butyl —S(O)₂— isopropyl —OH 1 n-butyl —S(O)₂— isopropyl—OH 2 n-butyl —S(O)₂— isopropyl —OH 3 n-butyl —S(O)₂— isopropyl —OCH₃ 1n-butyl —S(O)₂— isopropyl —OCH₃ 2 n-butyl —S(O)₂— isopropyl —OCH₃ 3n-butyl —S(O)₂— phenyl —OH 1 n-butyl —S(O)₂— phenyl —OH 2 n-butyl—S(O)₂— phenyl —OH 3 n-butyl —S(O)₂— phenyl —OCH₃ 1 n-butyl —S(O)₂—phenyl —OCH₃ 2 n-butyl —S(O)₂— phenyl —OCH₃ 3 n-butyl —C(O)—NH— methyl—OH 1 n-butyl —C(O)—NH— methyl —OH 2 n-butyl —C(O)—NH— methyl —OH 3n-butyl —C(O)—NH— methyl —OCH₃ 1 n-butyl —C(O)—NH— methyl —OCH₃ 2n-butyl —C(O)—NH— methyl —OCH₃ 3 n-butyl —C(O)—NH— ethyl —OH 1 n-butyl—C(O)—NH— ethyl —OH 2 n-butyl —C(O)—NH— ethyl —OH 3 n-butyl —C(O)—NH—ethyl —OCH₃ 1 n-butyl —C(O)—NH— ethyl —OCH₃ 2 n-butyl —C(O)—NH— ethyl—OCH₃ 3 n-butyl —C(O)—NH— isopropyl —OH 1 n-butyl —C(O)—NH— isopropyl—OH 2 n-butyl —C(O)—NH— isopropyl —OH 3 n-butyl —C(O)—NH— isopropyl—OCH₃ 1 n-butyl —C(O)—NH— isopropyl —OCH₃ 2 n-butyl —C(O)—NH— isopropyl—OCH₃ 3 n-butyl —C(O)—NH— phenyl —OH 1 n-butyl —C(O)—NH— phenyl —OH 2n-butyl —C(O)—NH— phenyl —OH 3 n-butyl —C(O)—NH— phenyl —OCH₃ 1 n-butyl—C(O)—NH— phenyl —OCH₃ 2 n-butyl —C(O)—NH— phenyl —OCH₃ 3 ethoxymethylBond methyl —OH 1 ethoxymethyl Bond methyl —OH 2 ethoxymethyl Bondmethyl —OH 3 ethoxymethyl Bond methyl —OCH₃ 1 ethoxymethyl Bond methyl—OCH₃ 2 ethoxymethyl Bond methyl —OCH₃ 3 ethoxymethyl Bond ethyl —OH 1ethoxymethyl Bond ethyl —OH 2 ethoxymethyl Bond ethyl —OH 3 ethoxymethylBond ethyl —OCH₃ 1 ethoxymethyl Bond ethyl —OCH₃ 2 ethoxymethyl Bondethyl —OCH₃ 3 ethoxymethyl Bond isopropyl —OH 1 ethoxymethyl Bondisopropyl —OH 2 ethoxymethyl Bond isopropyl —OH 3 ethoxymethyl Bondisopropyl —OCH₃ 1 ethoxymethyl Bond isopropyl —OCH₃ 2 ethoxymethyl Bondisopropyl —OCH₃ 3 ethoxymethyl Bond phenyl —OH 1 ethoxymethyl Bondphenyl —OH 2 ethoxymethyl Bond phenyl —OH 3 ethoxymethyl Bond phenyl—OCH₃ 1 ethoxymethyl Bond phenyl —OCH₃ 2 ethoxymethyl Bond phenyl —OCH₃3 ethoxymethyl —C(O)— methyl —OH 1 ethoxymethyl —C(O)— methyl —OH 2ethoxymethyl —C(O)— methyl —OH 3 ethoxymethyl —C(O)— methyl —OCH₃ 1ethoxymethyl —C(O)— methyl —OCH₃ 2 ethoxymethyl —C(O)— methyl —OCH₃ 3ethoxymethyl —C(O)— ethyl —OH 1 ethoxymethyl —C(O)— ethyl —OH 2ethoxymethyl —C(O)— ethyl —OH 3 ethoxymethyl —C(O)— ethyl —OCH₃ 1ethoxymethyl —C(O)— ethyl —OCH₃ 2 ethoxymethyl —C(O)— ethyl —OCH₃ 3ethoxymethyl —C(O)— isopropyl —OH 1 ethoxymethyl —C(O)— isopropyl —OH 2ethoxymethyl —C(O)— isopropyl —OH 3 ethoxymethyl —C(O)— isopropyl —OCH₃1 ethoxymethyl —C(O)— isopropyl —OCH₃ 2 ethoxymethyl —C(O)— isopropyl—OCH₃ 3 ethoxymethyl —C(O)— phenyl —OH 1 ethoxymethyl —C(O)— phenyl —OH2 ethoxymethyl —C(O)— phenyl —OH 3 ethoxymethyl —C(O)— phenyl —OCH₃ 1ethoxymethyl —C(O)— phenyl —OCH₃ 2 ethoxymethyl —C(O)— phenyl —OCH₃ 3ethoxymethyl —S(O)₂— methyl —OH 1 ethoxymethyl —S(O)₂— methyl —OH 2ethoxymethyl —S(O)₂— methyl —OH 3 ethoxymethyl —S(O)₂— methyl —OCH₃ 1ethoxymethyl —S(O)₂— methyl —OCH₃ 2 ethoxymethyl —S(O)₂— methyl —OCH₃ 3ethoxymethyl —S(O)₂— ethyl —OH 1 ethoxymethyl —S(O)₂— ethyl —OH 2ethoxymethyl —S(O)₂— ethyl —OH 3 ethoxymethyl —S(O)₂— ethyl —OCH₃ 1ethoxymethyl —S(O)₂— ethyl —OCH₃ 2 ethoxymethyl —S(O)₂— ethyl —OCH₃ 3ethoxymethyl —S(O)₂— isopropyl —OH 1 ethoxymethyl —S(O)₂— isopropyl —OH2 ethoxymethyl —S(O)₂— isopropyl —OH 3 ethoxymethyl —S(O)₂— isopropyl—OCH₃ 1 ethoxymethyl —S(O)₂— isopropyl —OCH₃ 2 ethoxymethyl —S(O)₂—isopropyl —OCH₃ 3 ethoxymethyl —S(O)₂— phenyl —OH 1 ethoxymethyl —S(O)₂—phenyl —OH 2 ethoxymethyl —S(O)₂— phenyl —OH 3 ethoxymethyl —S(O)₂—phenyl —OCH₃ 1 ethoxymethyl —S(O)₂— phenyl —OCH₃ 2 ethoxymethyl —S(O)₂—phenyl —OCH₃ 3 ethoxymethyl —C(O)—NH— methyl —OH 1 ethoxymethyl—C(O)—NH— methyl —OH 2 ethoxymethyl —C(O)—NH— methyl —OH 3 ethoxymethyl—C(O)—NH— methyl —OCH₃ 1 ethoxymethyl —C(O)—NH— methyl —OCH₃ 2ethoxymethyl —C(O)—NH— methyl —OCH₃ 3 ethoxymethyl —C(O)—NH— ethyl —OH 1ethoxymethyl —C(O)—NH— ethyl —OH 2 ethoxymethyl —C(O)—NH— ethyl —OH 3ethoxymethyl —C(O)—NH— ethyl —OCH₃ 1 ethoxymethyl —C(O)—NH— ethyl —OCH₃2 ethoxymethyl —C(O)—NH— ethyl —OCH₃ 3 ethoxymethyl —C(O)—NH— isopropyl—OH 1 ethoxymethyl —C(O)—NH— isopropyl —OH 2 ethoxymethyl —C(O)—NH—isopropyl —OH 3 ethoxymethyl —C(O)—NH— isopropyl —OCH₃ 1 ethoxymethyl—C(O)—NH— isopropyl —OCH₃ 2 ethoxymethyl —C(O)—NH— isopropyl —OCH₃ 3ethoxymethyl —C(O)—NH— phenyl —OH 1 ethoxymethyl —C(O)—NH— phenyl —OH 2ethoxymethyl —C(O)—NH— phenyl —OH 3 ethoxymethyl —C(O)—NH— phenyl —OCH₃1 ethoxymethyl —C(O)—NH— phenyl —OCH₃ 2 ethoxymethyl —C(O)—NH— phenyl—OCH₃ 3 2-methoxyethyl Bond methyl —OH 1 2-methoxyethyl Bond methyl —OH2 2-methoxyethyl Bond methyl —OH 3 2-methoxyethyl Bond methyl —OCH₃ 12-methoxyethyl Bond methyl —OCH₃ 2 2-methoxyethyl Bond methyl —OCH₃ 32-methoxyethyl Bond ethyl —OH 1 2-methoxyethyl Bond ethyl —OH 22-methoxyethyl Bond ethyl —OH 3 2-methoxyethyl Bond ethyl —OCH₃ 12-methoxyethyl Bond ethyl —OCH₃ 2 2-methoxyethyl Bond ethyl —OCH₃ 32-methoxyethyl Bond isopropyl —OH 1 2-methoxyethyl Bond isopropyl —OH 22-methoxyethyl Bond isopropyl —OH 3 2-methoxyethyl Bond isopropyl —OCH₃1 2-methoxyethyl Bond isopropyl —OCH₃ 2 2-methoxyethyl Bond isopropyl—OCH₃ 3 2-methoxyethyl Bond phenyl —OH 1 2-methoxyethyl Bond phenyl —OH2 2-methoxyethyl Bond phenyl —OH 3 2-methoxyethyl Bond phenyl —OCH₃ 12-methoxyethyl Bond phenyl —OCH₃ 2 2-methoxyethyl Bond phenyl —OCH₃ 32-methoxyethyl —C(O)— methyl —OH 1 2-methoxyethyl —C(O)— methyl —OH 22-methoxyethyl —C(O)— methyl —OH 3 2-methoxyethyl —C(O)— methyl —OCH₃ 12-methoxyethyl —C(O)— methyl —OCH₃ 2 2-methoxyethyl —C(O)— methyl —OCH₃3 2-methoxyethyl —C(O)— ethyl —OH 1 2-methoxyethyl —C(O)— ethyl —OH 22-methoxyethyl —C(O)— ethyl —OH 3 2-methoxyethyl —C(O)— ethyl —OCH₃ 12-methoxyethyl —C(O)— ethyl —OCH₃ 2 2-methoxyethyl —C(O)— ethyl —OCH₃ 32-methoxyethyl —C(O)— isopropyl —OH 1 2-methoxyethyl —C(O)— isopropyl—OH 2 2-methoxyethyl —C(O)— isopropyl —OH 3 2-methoxyethyl —C(O)—isopropyl —OCH₃ 1 2-methoxyethyl —C(O)— isopropyl —OCH₃ 2 2-methoxyethyl—C(O)— isopropyl —OCH₃ 3 2-methoxyethyl —C(O)— phenyl —OH 12-methoxyethyl —C(O)— phenyl —OH 2 2-methoxyethyl —C(O)— phenyl —OH 32-methoxyethyl —C(O)— phenyl —OCH₃ 1 2-methoxyethyl —C(O)— phenyl —OCH₃2 2-methoxyethyl —C(O)— phenyl —OCH₃ 3 2-methoxyethyl —S(O)₂— methyl —OH1 2-methoxyethyl —S(O)₂— methyl —OH 2 2-methoxyethyl —S(O)₂— methyl —OH3 2-methoxyethyl —S(O)₂— methyl —OCH₃ 1 2-methoxyethyl —S(O)₂— methyl—OCH₃ 2 2-methoxyethyl —S(O)₂— methyl —OCH₃ 3 2-methoxyethyl —S(O)₂—ethyl —OH 1 2-methoxyethyl —S(O)₂— ethyl —OH 2 2-methoxyethyl —S(O)₂—ethyl —OH 3 2-methoxyethyl —S(O)₂— ethyl —OCH₃ 1 2-methoxyethyl —S(O)₂—ethyl —OCH₃ 2 2-methoxyethyl —S(O)₂— ethyl —OCH₃ 3 2-methoxyethyl—S(O)₂— isopropyl —OH 1 2-methoxyethyl —S(O)₂— isopropyl —OH 22-methoxyethyl —S(O)₂— isopropyl —OH 3 2-methoxyethyl —S(O)₂— isopropyl—OCH₃ 1 2-methoxyethyl —S(O)₂— isopropyl —OCH₃ 2 2-methoxyethyl —S(O)₂—isopropyl —OCH₃ 3 2-methoxyethyl —S(O)₂— phenyl —OH 1 2-methoxyethyl—S(O)₂— phenyl —OH 2 2-methoxyethyl —S(O)₂— phenyl —OH 3 2-methoxyethyl—S(O)₂— phenyl —OCH₃ 1 2-methoxyethyl —S(O)₂— phenyl —OCH₃ 22-methoxyethyl —S(O)₂— phenyl —OCH₃ 3 2-methoxyethyl —C(O)—NH— methyl—OH 1 2-methoxyethyl —C(O)—NH— methyl —OH 2 2-methoxyethyl —C(O)—NH—methyl —OH 3 2-methoxyethyl —C(O)—NH— methyl —OCH₃ 1 2-methoxyethyl—C(O)—NH— methyl —OCH₃ 2 2-methoxyethyl —C(O)—NH— methyl —OCH₃ 32-methoxyethyl —C(O)—NH— ethyl —OH 1 2-methoxyethyl —C(O)—NH— ethyl —OH2 2-methoxyethyl —C(O)—NH— ethyl —OH 3 2-methoxyethyl —C(O)—NH— ethyl—OCH₃ 1 2-methoxyethyl —C(O)—NH— ethyl —OCH₃ 2 2-methoxyethyl —C(O)—NH—ethyl —OCH₃ 3 2-methoxyethyl —C(O)—NH— isopropyl —OH 1 2-methoxyethyl—C(O)—NH— isopropyl —OH 2 2-methoxyethyl —C(O)—NH— isopropyl —OH 32-methoxyethyl —C(O)—NH— isopropyl —OCH₃ 1 2-methoxyethyl —C(O)—NH—isopropyl —OCH₃ 2 2-methoxyethyl —C(O)—NH— isopropyl —OCH₃ 32-methoxyethyl —C(O)—NH— phenyl —OH 1 2-methoxyethyl —C(O)—NH— phenyl—OH 2 2-methoxyethyl —C(O)—NH— phenyl —OH 3 2-methoxyethyl —C(O)—NH—phenyl —OCH₃ 1 2-methoxyethyl —C(O)—NH— phenyl —OCH₃ 2 2-methoxyethyl—C(O)—NH— phenyl —OCH₃ 3Exemplary Compounds Table 3

Certain exemplary compounds, including some of those described above inthe Examples, have the following Formulas (II-3, III-3, IV-3, and V-3)wherein R₂, Z, Q, R₄, and m are defined immediately below in the table.In this table, for each ring system, each row represents one specificcompound.

R₂ Q Z R₄ m H Bond —CH₂CH₂CH₂— methyl 1 H Bond —CH₂CH₂CH₂— methyl 2 HBond —CH₂CH₂CH₂— methyl 3 H Bond —CH₂CH₂CH₂— ethyl 1 H Bond —CH₂CH₂CH₂—ethyl 2 H Bond —CH₂CH₂CH₂— ethyl 3 H Bond —CH₂—O—CH₂— methyl 1 H Bond—CH₂—O—CH₂— methyl 2 H Bond —CH₂—O—CH₂— methyl 3 H Bond —CH₂—O—CH₂—ethyl 1 H Bond —CH₂—O—CH₂— ethyl 2 H Bond —CH₂—O—CH₂— ethyl 3 H —C(O)——CH₂CH₂CH₂— methyl 1 H —C(O)— —CH₂CH₂CH₂— methyl 2 H —C(O)— —CH₂CH₂CH₂—methyl 3 H —C(O)— —CH₂CH₂CH₂— ethyl 1 H —C(O)— —CH₂CH₂CH₂— ethyl 2 H—C(O)— —CH₂CH₂CH₂— ethyl 3 H —C(O)— —CH₂—O—CH₂— methyl 1 H —C(O)——CH₂—O—CH₂— methyl 2 H —C(O)— —CH₂—O—CH₂— methyl 3 H —C(O)— —CH₂—O—CH₂—ethyl 1 H —C(O)— —CH₂—O—CH₂— ethyl 2 H —C(O)— —CH₂—O—CH₂— ethyl 3 H—S(O)₂— —CH₂CH₂CH₂— methyl 1 H —S(O)₂— —CH₂CH₂CH₂— methyl 2 H —S(O)₂——CH₂CH₂CH₂— methyl 3 H —S(O)₂— —CH₂CH₂CH₂— ethyl 1 H —S(O)₂— —CH₂CH₂CH₂—ethyl 2 H —S(O)₂— —CH₂CH₂CH₂— ethyl 3 H —S(O)₂— —CH₂—O—CH₂— methyl 1 H—S(O)₂— —CH₂—O—CH₂— methyl 2 H —S(O)₂— —CH₂—O—CH₂— methyl 3 H —S(O)₂——CH₂—O—CH₂— ethyl 1 H —S(O)₂— —CH₂—O—CH₂— ethyl 2 H —S(O)₂— —CH₂—O—CH₂—ethyl 3 H —C(O)—NH— —CH₂CH₂CH₂— methyl 1 H —C(O)—NH— —CH₂CH₂CH₂— methyl2 H —C(O)—NH— —CH₂CH₂CH₂— methyl 3 H —C(O)—NH— —CH₂CH₂CH₂— ethyl 1 H—C(O)—NH— —CH₂CH₂CH₂— ethyl 2 H —C(O)—NH— —CH₂CH₂CH₂— ethyl 3 H—C(O)—NH— —CH₂—O—CH₂— methyl 1 H —C(O)—NH— —CH₂—O—CH₂— methyl 2 H—C(O)—NH— —CH₂—O—CH₂— methyl 3 H —C(O)—NH— —CH₂—O—CH₂— ethyl 1 H—C(O)—NH— —CH₂—O—CH₂— ethyl 2 H —C(O)—NH— —CH₂—O—CH₂— ethyl 3 methylBond —CH₂CH₂CH₂— methyl 1 methyl Bond —CH₂CH₂CH₂— methyl 2 methyl Bond—CH₂CH₂CH₂— methyl 3 methyl Bond —CH₂CH₂CH₂— ethyl 1 methyl Bond—CH₂CH₂CH₂— ethyl 2 methyl Bond —CH₂CH₂CH₂— ethyl 3 methyl Bond—CH₂—O—CH₂— methyl 1 methyl Bond —CH₂—O—CH₂— methyl 2 methyl Bond—CH₂—O—CH₂— methyl 3 methyl Bond —CH₂—O—CH₂— ethyl 1 methyl Bond—CH₂—O—CH₂— ethyl 2 methyl Bond —CH₂—O—CH₂— ethyl 3 methyl —C(O)——CH₂CH₂CH₂— methyl 1 methyl —C(O)— —CH₂CH₂CH₂— methyl 2 methyl —C(O)——CH₂CH₂CH₂— methyl 3 methyl —C(O)— —CH₂CH₂CH₂— ethyl 1 methyl —C(O)——CH₂CH₂CH₂— ethyl 2 methyl —C(O)— —CH₂CH₂CH₂— ethyl 3 methyl —C(O)——CH₂—O—CH₂— methyl 1 methyl —C(O)— —CH₂—O—CH₂— methyl 2 methyl —C(O)——CH₂—O—CH₂— methyl 3 methyl —C(O)— —CH₂—O—CH₂— ethyl 1 methyl —C(O)——CH₂—O—CH₂— ethyl 2 methyl —C(O)— —CH₂—O—CH₂— ethyl 3 methyl —S(O)₂——CH₂CH₂CH₂— methyl 1 methyl —S(O)₂— —CH₂CH₂CH₂— methyl 2 methyl —S(O)₂——CH₂CH₂CH₂— methyl 3 methyl —S(O)₂— —CH₂CH₂CH₂— ethyl 1 methyl —S(O)₂——CH₂CH₂CH₂— ethyl 2 methyl —S(O)₂— —CH₂CH₂CH₂— ethyl 3 methyl —S(O)₂——CH₂—O—CH₂— methyl 1 methyl —S(O)₂— —CH₂—O—CH₂— methyl 2 methyl —S(O)₂——CH₂—O—CH₂— methyl 3 methyl —S(O)₂— —CH₂—O—CH₂— ethyl 1 methyl —S(O)₂——CH₂—O—CH₂— ethyl 2 methyl —S(O)₂— —CH₂—O—CH₂— ethyl 3 methyl —C(O)—NH——CH₂CH₂CH₂— methyl 1 methyl —C(O)—NH— —CH₂CH₂CH₂— methyl 2 methyl—C(O)—NH— —CH₂CH₂CH₂— methyl 3 methyl —C(O)—NH— —CH₂CH₂CH₂— ethyl 1methyl —C(O)—NH— —CH₂CH₂CH₂— ethyl 2 methyl —C(O)—NH— —CH₂CH₂CH₂— ethyl3 methyl —C(O)—NH— —CH₂—O—CH₂— methyl 1 methyl —C(O)—NH— —CH₂—O—CH₂—methyl 2 methyl —C(O)—NH— —CH₂—O—CH₂— methyl 3 methyl —C(O)—NH——CH₂—O—CH₂— ethyl 1 methyl —C(O)—NH— —CH₂—O—CH₂— ethyl 2 methyl—C(O)—NH— —CH₂—O—CH₂— ethyl 3 ethyl Bond —CH₂CH₂CH₂— methyl 1 ethyl Bond—CH₂CH₂CH₂— methyl 2 ethyl Bond —CH₂CH₂CH₂— methyl 3 ethyl Bond—CH₂CH₂CH₂— ethyl 1 ethyl Bond —CH₂CH₂CH₂— ethyl 2 ethyl Bond—CH₂CH₂CH₂— ethyl 3 ethyl Bond —CH₂—O—CH₂— methyl 1 ethyl Bond—CH₂—O—CH₂— methyl 2 ethyl Bond —CH₂—O—CH₂— methyl 3 ethyl Bond—CH₂—O—CH₂— ethyl 1 ethyl Bond —CH₂—O—CH₂— ethyl 2 ethyl Bond—CH₂—O—CH₂— ethyl 3 ethyl —C(O)— —CH₂CH₂CH₂— methyl 1 ethyl —C(O)——CH₂CH₂CH₂— methyl 2 ethyl —C(O)— —CH₂CH₂CH₂— methyl 3 ethyl —C(O)——CH₂CH₂CH₂— ethyl 1 ethyl —C(O)— —CH₂CH₂CH₂— ethyl 2 ethyl —C(O)——CH₂CH₂CH₂— ethyl 3 ethyl —C(O)— —CH₂—O—CH₂— methyl 1 ethyl —C(O)——CH₂—O—CH₂— methyl 2 ethyl —C(O)— —CH₂—O—CH₂— methyl 3 ethyl —C(O)——CH₂—O—CH₂— ethyl 1 ethyl —C(O)— —CH₂—O—CH₂— ethyl 2 ethyl —C(O)——CH₂—O—CH₂— ethyl 3 ethyl —S(O)₂— —CH₂CH₂CH₂— methyl 1 ethyl —S(O)₂——CH₂CH₂CH₂— methyl 2 ethyl —S(O)₂— —CH₂CH₂CH₂— methyl 3 ethyl —S(O)₂——CH₂CH₂CH₂— ethyl 1 ethyl —S(O)₂— —CH₂CH₂CH₂— ethyl 2 ethyl —S(O)₂——CH₂CH₂CH₂— ethyl 3 ethyl —S(O)₂— —CH₂—O—CH₂— methyl 1 ethyl —S(O)₂——CH₂—O—CH₂— methyl 2 ethyl —S(O)₂— —CH₂—O—CH₂— methyl 3 ethyl —S(O)₂——CH₂—O—CH₂— ethyl 1 ethyl —S(O)₂— —CH₂—O—CH₂— ethyl 2 ethyl —S(O)₂——CH₂—O—CH₂— ethyl 3 ethyl —C(O)—NH— —CH₂CH₂CH₂— methyl 1 ethyl —C(O)—NH——CH₂CH₂CH₂— methyl 2 ethyl —C(O)—NH— —CH₂CH₂CH₂— methyl 3 ethyl—C(O)—NH— —CH₂CH₂CH₂— ethyl 1 ethyl —C(O)—NH— —CH₂CH₂CH₂— ethyl 2 ethyl—C(O)—NH— —CH₂CH₂CH₂— ethyl 3 ethyl —C(O)—NH— —CH₂—O—CH₂— methyl 1 ethyl—C(O)—NH— —CH₂—O—CH₂— methyl 2 ethyl —C(O)—NH— —CH₂—O—CH₂— methyl 3ethyl —C(O)—NH— —CH₂—O—CH₂— ethyl 1 ethyl —C(O)—NH— —CH₂—O—CH₂— ethyl 2ethyl —C(O)—NH— —CH₂—O—CH₂— ethyl 3 n-propyl Bond —CH₂CH₂CH₂— methyl 1n-propyl Bond —CH₂CH₂CH₂— methyl 2 n-propyl Bond —CH₂CH₂CH₂— methyl 3n-propyl Bond —CH₂CH₂CH₂— ethyl 1 n-propyl Bond —CH₂CH₂CH₂— ethyl 2n-propyl Bond —CH₂CH₂CH₂— ethyl 3 n-propyl Bond —CH₂—O—CH₂— methyl 1n-propyl Bond —CH₂—O—CH₂— methyl 2 n-propyl Bond —CH₂—O—CH₂— methyl 3n-propyl Bond —CH₂—O—CH₂— ethyl 1 n-propyl Bond —CH₂—O—CH₂— ethyl 2n-propyl Bond —CH₂—O—CH₂— ethyl 3 n-propyl —C(O)— —CH₂CH₂CH₂— methyl 1n-propyl —C(O)— —CH₂CH₂CH₂— methyl 2 n-propyl —C(O)— —CH₂CH₂CH₂— methyl3 n-propyl —C(O)— —CH₂CH₂CH₂— ethyl 1 n-propyl —C(O)— —CH₂CH₂CH₂— ethyl2 n-propyl —C(O)— —CH₂CH₂CH₂— ethyl 3 n-propyl —C(O)— —CH₂—O—CH₂— methyl1 n-propyl —C(O)— —CH₂—O—CH₂— methyl 2 n-propyl —C(O)— —CH₂—O—CH₂—methyl 3 n-propyl —C(O)— —CH₂—O—CH₂— ethyl 1 n-propyl —C(O)— —CH₂—O—CH₂—ethyl 2 n-propyl —C(O)— —CH₂—O—CH₂— ethyl 3 n-propyl —S(O)₂— —CH₂CH₂CH₂—methyl 1 n-propyl —S(O)₂— —CH₂CH₂CH₂— methyl 2 n-propyl —S(O)₂——CH₂CH₂CH₂— methyl 3 n-propyl —S(O)₂— —CH₂CH₂CH₂— ethyl 1 n-propyl—S(O)₂— —CH₂CH₂CH₂— ethyl 2 n-propyl —S(O)₂— —CH₂CH₂CH₂— ethyl 3n-propyl —S(O)₂— —CH₂—O—CH₂— methyl 1 n-propyl —S(O)₂— —CH₂—O—CH₂—methyl 2 n-propyl —S(O)₂— —CH₂—O—CH₂— methyl 3 n-propyl —S(O)₂——CH₂—O—CH₂— ethyl 1 n-propyl —S(O)₂— —CH₂—O—CH₂— ethyl 2 n-propyl—S(O)₂— —CH₂—O—CH₂— ethyl 3 n-propyl —C(O)—NH— —CH₂CH₂CH₂— methyl 1n-propyl —C(O)—NH— —CH₂CH₂CH₂— methyl 2 n-propyl —C(O)—NH— —CH₂CH₂CH₂—methyl 3 n-propyl —C(O)—NH— —CH₂CH₂CH₂— ethyl 1 n-propyl —C(O)—NH——CH₂CH₂CH₂— ethyl 2 n-propyl —C(O)—NH— —CH₂CH₂CH₂— ethyl 3 n-propyl—C(O)—NH— —CH₂—O—CH₂— methyl 1 n-propyl —C(O)—NH— —CH₂—O—CH₂— methyl 2n-propyl —C(O)—NH— —CH₂—O—CH₂— methyl 3 n-propyl —C(O)—NH— —CH₂—O—CH₂—ethyl 1 n-propyl —C(O)—NH— —CH₂—O—CH₂— ethyl 2 n-propyl —C(O)—NH——CH₂—O—CH₂— ethyl 3 n-butyl Bond —CH₂CH₂CH₂— methyl 1 n-butyl Bond—CH₂CH₂CH₂— methyl 2 n-butyl Bond —CH₂CH₂CH₂— methyl 3 n-butyl Bond—CH₂CH₂CH₂— ethyl 1 n-butyl Bond —CH₂CH₂CH₂— ethyl 2 n-butyl Bond—CH₂CH₂CH₂— ethyl 3 n-butyl Bond —CH₂—O—CH₂— methyl 1 n-butyl Bond—CH₂—O—CH₂— methyl 2 n-butyl Bond —CH₂—O—CH₂— methyl 3 n-butyl Bond—CH₂—O—CH₂— ethyl 1 n-butyl Bond —CH₂—O—CH₂— ethyl 2 n-butyl Bond—CH₂—O—CH₂— ethyl 3 n-butyl —C(O)— —CH₂CH₂CH₂— methyl 1 n-butyl —C(O)——CH₂CH₂CH₂— methyl 2 n-butyl —C(O)— —CH₂CH₂CH₂— methyl 3 n-butyl —C(O)——CH₂CH₂CH₂— ethyl 1 n-butyl —C(O)— —CH₂CH₂CH₂— ethyl 2 n-butyl —C(O)——CH₂CH₂CH₂— ethyl 3 n-butyl —C(O)— —CH₂—O—CH₂— methyl 1 n-butyl —C(O)——CH₂—O—CH₂— methyl 2 n-butyl —C(O)— —CH₂—O—CH₂— methyl 3 n-butyl —C(O)——CH₂—O—CH₂— ethyl 1 n-butyl —C(O)— —CH₂—O—CH₂— ethyl 2 n-butyl —C(O)——CH₂—O—CH₂— ethyl 3 n-butyl —S(O)₂— —CH₂CH₂CH₂— methyl 1 n-butyl —S(O)₂——CH₂CH₂CH₂— methyl 2 n-butyl —S(O)₂— —CH₂CH₂CH₂— methyl 3 n-butyl—S(O)₂— —CH₂CH₂CH₂— ethyl 1 n-butyl —S(O)₂— —CH₂CH₂CH₂— ethyl 2 n-butyl—S(O)₂— —CH₂CH₂CH₂— ethyl 3 n-butyl —S(O)₂— —CH₂—O—CH₂— methyl 1 n-butyl—S(O)₂— —CH₂—O—CH₂— methyl 2 n-butyl —S(O)₂— —CH₂—O—CH₂— methyl 3n-butyl —S(O)₂— —CH₂—O—CH₂— ethyl 1 n-butyl —S(O)₂— —CH₂—O—CH₂— ethyl 2n-butyl —S(O)₂— —CH₂—O—CH₂— ethyl 3 n-butyl —C(O)—NH— —CH₂CH₂CH₂— methyl1 n-butyl —C(O)—NH— —CH₂CH₂CH₂— methyl 2 n-butyl —C(O)—NH— —CH₂CH₂CH₂—methyl 3 n-butyl —C(O)—NH— —CH₂CH₂CH₂— ethyl 1 n-butyl —C(O)—NH——CH₂CH₂CH₂— ethyl 2 n-butyl —C(O)—NH— —CH₂CH₂CH₂— ethyl 3 n-butyl—C(O)—NH— —CH₂—O—CH₂— methyl 1 n-butyl —C(O)—NH— —CH₂—O—CH₂— methyl 2n-butyl —C(O)—NH— —CH₂—O—CH₂— methyl 3 n-butyl —C(O)—NH— —CH₂—O—CH₂—ethyl 1 n-butyl —C(O)—NH— —CH₂—O—CH₂— ethyl 2 n-butyl —C(O)—NH——CH₂—O—CH₂— ethyl 3 ethoxymethyl Bond —CH₂CH₂CH₂— methyl 1 ethoxymethylBond —CH₂CH₂CH₂— methyl 2 ethoxymethyl Bond —CH₂CH₂CH₂— methyl 3ethoxymethyl Bond —CH₂CH₂CH₂— ethyl 1 ethoxymethyl Bond —CH₂CH₂CH₂—ethyl 2 ethoxymethyl Bond —CH₂CH₂CH₂— ethyl 3 ethoxymethyl Bond—CH₂—O—CH₂— methyl 1 ethoxymethyl Bond —CH₂—O—CH₂— methyl 2 ethoxymethylBond —CH₂—O—CH₂— methyl 3 ethoxymethyl Bond —CH₂—O—CH₂— ethyl 1ethoxymethyl Bond —CH₂—O—CH₂— ethyl 2 ethoxymethyl Bond —CH₂—O—CH₂—ethyl 3 ethoxymethyl —C(O)— —CH₂CH₂CH₂— methyl 1 ethoxymethyl —C(O)——CH₂CH₂CH₂— methyl 2 ethoxymethyl —C(O)— —CH₂CH₂CH₂— methyl 3ethoxymethyl —C(O)— —CH₂CH₂CH₂— ethyl 1 ethoxymethyl —C(O)— —CH₂CH₂CH₂—ethyl 2 ethoxymethyl —C(O)— —CH₂CH₂CH₂— ethyl 3 ethoxymethyl —C(O)——CH₂—O—CH₂— methyl 1 ethoxymethyl —C(O)— —CH₂—O—CH₂— methyl 2ethoxymethyl —C(O)— —CH₂—O—CH₂— methyl 3 ethoxymethyl —C(O)— —CH₂—O—CH₂—ethyl 1 ethoxymethyl —C(O)— —CH₂—O—CH₂— ethyl 2 ethoxymethyl —C(O)——CH₂—O—CH₂— ethyl 3 ethoxymethyl —S(O)₂— —CH₂CH₂CH₂— methyl 1ethoxymethyl —S(O)₂— —CH₂CH₂CH₂— methyl 2 ethoxymethyl —S(O)₂——CH₂CH₂CH₂— methyl 3 ethoxymethyl —S(O)₂— —CH₂CH₂CH₂— ethyl 1ethoxymethyl —S(O)₂— —CH₂CH₂CH₂— ethyl 2 ethoxymethyl —S(O)₂——CH₂CH₂CH₂— ethyl 3 ethoxymethyl —S(O)₂— —CH₂—O—CH₂— methyl 1ethoxymethyl —S(O)₂— —CH₂—O—CH₂— methyl 2 ethoxymethyl —S(O)₂——CH₂—O—CH₂— methyl 3 ethoxymethyl —S(O)₂— —CH₂—O—CH₂— ethyl 1ethoxymethyl —S(O)₂— —CH₂—O—CH₂— ethyl 2 ethoxymethyl —S(O)₂——CH₂—O—CH₂— ethyl 3 ethoxymethyl —C(O)—NH— —CH₂CH₂CH₂— methyl 1ethoxymethyl —C(O)—NH— —CH₂CH₂CH₂— methyl 2 ethoxymethyl —C(O)—NH——CH₂CH₂CH₂— methyl 3 ethoxymethyl —C(O)—NH— —CH₂CH₂CH₂— ethyl 1ethoxymethyl —C(O)—NH— —CH₂CH₂CH₂— ethyl 2 ethoxymethyl —C(O)—NH——CH₂CH₂CH₂— ethyl 3 ethoxymethyl —C(O)—NH— —CH₂—O—CH₂— methyl 1ethoxymethyl —C(O)—NH— —CH₂—O—CH₂— methyl 2 ethoxymethyl —C(O)—NH——CH₂—O—CH₂— methyl 3 ethoxymethyl —C(O)—NH— —CH₂—O—CH₂— ethyl 1ethoxymethyl —C(O)—NH— —CH₂—O—CH₂— ethyl 2 ethoxymethyl —C(O)—NH——CH₂—O—CH₂— ethyl 3 2-methoxyethyl Bond —CH₂CH₂CH₂— methyl 12-methoxyethyl Bond —CH₂CH₂CH₂— methyl 2 2-methoxyethyl Bond —CH₂CH₂CH₂—methyl 3 2-methoxyethyl Bond —CH₂CH₂CH₂— ethyl 1 2-methoxyethyl Bond—CH₂CH₂CH₂— ethyl 2 2-methoxyethyl Bond —CH₂CH₂CH₂— ethyl 32-methoxyethyl Bond —CH₂—O—CH₂— methyl 1 2-methoxyethyl Bond —CH₂—O—CH₂—methyl 2 2-methoxyethyl Bond —CH₂—O—CH₂— methyl 3 2-methoxyethyl Bond—CH₂—O—CH₂— ethyl 1 2-methoxyethyl Bond —CH₂—O—CH₂— ethyl 22-methoxyethyl Bond —CH₂—O—CH₂— ethyl 3 2-methoxyethyl —C(O)——CH₂CH₂CH₂— methyl 1 2-methoxyethyl —C(O)— —CH₂CH₂CH₂— methyl 22-methoxyethyl —C(O)— —CH₂CH₂CH₂— methyl 3 2-methoxyethyl —C(O)——CH₂CH₂CH₂— ethyl 1 2-methoxyethyl —C(O)— —CH₂CH₂CH₂— ethyl 22-methoxyethyl —C(O)— —CH₂CH₂CH₂— ethyl 3 2-methoxyethyl —C(O)——CH₂—O—CH₂— methyl 1 2-methoxyethyl —C(O)— —CH₂—O—CH₂— methyl 22-methoxyethyl —C(O)— —CH₂—O—CH₂— methyl 3 2-methoxyethyl —C(O)——CH₂—O—CH₂— ethyl 1 2-methoxyethyl —C(O)— —CH₂—O—CH₂— ethyl 22-methoxyethyl —C(O)— —CH₂—O—CH₂— ethyl 3 2-methoxyethyl —S(O)₂——CH₂CH₂CH₂— methyl 1 2-methoxyethyl —S(O)₂— —CH₂CH₂CH₂— methyl 22-methoxyethyl —S(O)₂— —CH₂CH₂CH₂— methyl 3 2-methoxyethyl —S(O)₂——CH₂CH₂CH₂— ethyl 1 2-methoxyethyl —S(O)₂— —CH₂CH₂CH₂— ethyl 22-methoxyethyl —S(O)₂— —CH₂CH₂CH₂— ethyl 3 2-methoxyethyl —S(O)₂——CH₂—O—CH₂— methyl 1 2-methoxyethyl —S(O)₂— —CH₂—O—CH₂— methyl 22-methoxyethyl —S(O)₂— —CH₂—O—CH₂— methyl 3 2-methoxyethyl —S(O)₂——CH₂—O—CH₂— ethyl 1 2-methoxyethyl —S(O)₂— —CH₂—O—CH₂— ethyl 22-methoxyethyl —S(O)₂— —CH₂—O—CH₂— ethyl 3 2-methoxyethyl —C(O)—NH——CH₂CH₂CH₂— methyl 1 2-methoxyethyl —C(O)—NH— —CH₂CH₂CH₂— methyl 22-methoxyethyl —C(O)—NH— —CH₂CH₂CH₂— methyl 3 2-methoxyethyl —C(O)—NH——CH₂CH₂CH₂— ethyl 1 2-methoxyethyl —C(O)—NH— —CH₂CH₂CH₂— ethyl 22-methoxyethyl —C(O)—NH— —CH₂CH₂CH₂— ethyl 3 2-methoxyethyl —C(O)—NH——CH₂—O—CH₂— methyl 1 2-methoxyethyl —C(O)—NH— —CH₂—O—CH₂— methyl 22-methoxyethyl —C(O)—NH— —CH₂—O—CH₂— methyl 3 2-methoxyethyl —C(O)—NH——CH₂—O—CH₂— ethyl 1 2-methoxyethyl —C(O)—NH— —CH₂—O—CH₂— ethyl 22-methoxyethyl —C(O)—NH— —CH₂—O—CH₂— ethyl 3Exemplary Compounds Table 4

Certain exemplary compounds, including some of those described above inthe Examples, have the following Formulas (II-4, III-4, IV-4, and V-4)wherein R₂, Z, and m are defined immediately below in the table. In thistable, for each ring system, each row represents one specific compound.

R₂ Z m hydroxymethyl BOND 1 hydroxymethyl BOND 2 2-hydroxyethyl BOND 12-hydroxyethyl BOND 2 hydroxymethyl —CH₂— 1 hydroxymethyl —CH₂— 22-hydroxyethyl —CH₂— 1 2-hydroxyethyl —CH₂— 2 hydroxymethyl —CH₂CH₂— 1hydroxymethyl —CH₂CH₂— 2 2-hydroxyethyl —CH₂CH₂— 1 2-hydroxyethyl—CH₂CH₂— 2 hydroxymethyl —CH₂CH₂CH₂— 1 hydroxymethyl —CH₂CH₂CH₂— 22-hydroxyethyl —CH₂CH₂CH₂— 1 2-hydroxyethyl —CH₂CH₂CH₂— 2 hydroxymethyl—CH₂—O—CH₂— 1 hydroxymethyl —CH₂—O—CH₂— 2 2-hydroxyethyl —CH₂—O—CH₂— 12-hydroxyethyl —CH₂—O—CH₂— 2 H —CH₂—O— 1 H —CH₂—O— 2 methyl —CH₂—O— 1methyl —CH₂—O— 2 ethyl —CH₂—O— 1 ethyl —CH₂—O— 2 n-propyl —CH₂—O— 1n-propyl —CH₂—O— 2 n-butyl —CH₂—O— 1 n-butyl —CH₂—O— 2 ethoxymethyl—CH₂—O— 1 ethoxymethyl —CH₂—O— 2 hydroxymethyl —CH₂—O— 1 hydroxymethyl—CH₂—O— 2 2-hydroxyethyl —CH₂—O— 1 2-hydroxyethyl —CH₂—O— 2 H —O— 1 H—O— 2 methyl —O— 1 methyl —O— 2 ethyl —O— 1 ethyl —O— 2 n-propyl —O— 1n-propyl —O— 2 n-butyl —O— 1 n-butyl —O— 2 ethoxymethyl —O— 1ethoxymethyl —O— 2 hydroxymethyl —O— 1 hydroxymethyl —O— 22-hydroxyethyl —O— 1 2-hydroxyethyl —O— 2Exemplary Compounds Table 5

Certain exemplary compounds, including some of those described above inthe Examples, have the following Formulas (II-5, III-5, IV-5, and V-5)wherein R₂, and m are defined immediately below in the table. In thistable, for each ring system, each row represents one specific compound.

R₂ m hydroxymethyl 1 hydroxymethyl 2 2-hydroxyethyl 1 2-hydroxyethyl 2

Compounds of the invention have been found to induce biosynthesis whentested using the method described below.

Cytokine Induction in Human Cells

An in vitro human blood cell system is used to assess cytokineinduction. Activity is based on the measurement of interferon (α) andtumor necrosis factor (a) (IFN-α and TNF-α, respectively) secreted intoculture media as described by Testerman et. al. in “Cytokine Inductionby the Immunomodulators Imiquimod and S-27609”, Journal of LeukocyteBiology, 58, 365-372 (September, 1995).

Blood Cell Preparation for Culture

Whole blood from healthy human donors is collected by venipuncture intovacutainer tubes or syringes containing EDTA. Peripheral bloodmononuclear cells (PBMC) are separated from whole blood by densitygradient centrifugation using HISTOPAQUE-1077 (Sigma, St. Louis, Mo.) orFicoll-Paque Plus (Amersham Biosciences Piscataway, N.J.). Blood isdiluted 1:1 with Dulbecco's Phosphate Buffered Saline (DPBS) or Hank'sBalanced Salts Solution (HBSS). Alternately, whole blood is placed inAccuspin (Sigma) or LeucoSep (Greiner Bio-One, Inc., Longwood, Fla.)centrifuge frit tubes containing density gradient medium. The PBMC layeris collected and washed twice with DPBS or HBSS and re-suspended at4×10⁶ cells/mL in RPMI complete. The PBMC suspension is added to 96 wellflat bottom sterile tissue culture plates containing an equal volume ofRPMI complete media containing test compound.

Compound Preparation

The compounds are solubilized in dimethyl sulfoxide (DMSO). The DMSOconcentration should not exceed a final concentration of 1% for additionto the culture wells. The compounds are generally tested atconcentrations ranging from 30-0.014 μM. Controls include cell sampleswith media only, cell samples with DMSO only (no compound), and cellsamples with reference compound.

Incubation

The solution of test compound is added at 60 μM to the first wellcontaining RPMI complete and serial 3 fold dilutions are made in thewells. The PBMC suspension is then added to the wells in an equalvolume, bringing the test compound concentrations to the desired range(usually 30-0.014 μM). The final concentration of PBMC suspension is2×10⁶ cells/mL. The plates are covered with sterile plastic lids, mixedgently and then incubated for 18 to 24 hours at 37° C. in a 5% carbondioxide atmosphere.

Separation

Following incubation the plates are centrifuged for 10 minutes at 1000rpm (approximately 200×g) at 4° C. The cell-free culture supernatant isremoved and transferred to sterile polypropylene tubes. Samples aremaintained at −30 to −70° C. until analysis. The samples are analyzedfor IFN-α by ELISA and for TNF-α by IGEN/BioVeris Assay.

Interferon (α) and Tumor Necrosis Factor (α) Analysis

IFN-α concentration is determined with a human multi-subtypecolorimetric sandwich ELISA (Catalog Number 41105) from PBL BiomedicalLaboratories, Piscataway, N.J. Results are expressed in pg/mL.

The TNF-α concentration is determined by ORIGEN M-Series Immunoassay andread on an IGEN M-8 analyzer from BioVeris Corporation, formerly knownas IGEN International, Gaithersburg, Md. The immunoassay uses a humanTNF-α capture and detection antibody pair (Catalog Numbers AHC3419 andAHC3712) from Biosource International, Camarillo, Calif. Results areexpressed in pg/mL.

Assay Data and Analysis

In total, the data output of the assay consists of concentration valuesof TNF-α and IFN-α (y-axis) as a function of compound concentration(x-axis).

Analysis of the data has two steps. First, the greater of the mean DMSO(DMSO control wells) or the experimental background (usually 20 pg/mLfor IFN-α and 40 pg/mL for TNF-α) is subtracted from each reading. Ifany negative values result from background subtraction, the reading isreported as “*”, and is noted as not reliably detectable. In subsequentcalculations and statistics, “*”, is treated as a zero. Second, allbackground subtracted values are multiplied by a single adjustment ratioto decrease experiment to experiment variability. The adjustment ratiois the area of the reference compound in the new experiment divided bythe expected area of the reference compound based on the past 61experiments (unadjusted readings). This results in the scaling of thereading (y-axis) for the new data without changing the shape of thedose-response curve. The reference compound used is2-[4-amino-2-ethoxymethyl-6,7,8,9-tetrahydro-α,α-dimethyl-1H-imidazo[4,5-c]quinolin-1-yl]ethanolhydrate (U.S. Pat. No. 5,352,784; Example 91) and the expected area isthe sum of the median dose values from the past 61 experiments.

The minimum effective concentration is calculated based on thebackground-subtracted, reference-adjusted results for a given experimentand compound. The minimum effective concentration (molar) is the lowestof the tested compound concentrations that induces a response over afixed cytokine concentration for the tested cytokine (usually 20 pg/mLfor IFN-α and 40 pg/mL for TNF-α). The maximal response is the maximalamount of cytokine (pg/ml) produced in the dose-response.

Cytokine Induction in Human Cells High Throughput Screen

The CYTOKINE INDUCTION IN HUMAN CELLS test method described above wasmodified as follows for high throughput screening.

Blood Cell Preparation for Culture

Whole blood from healthy human donors is collected by venipuncture intovacutainer tubes or syringes containing EDTA. Peripheral bloodmononuclear cells (PBMC) are separated from whole blood by densitygradient centrifugation using HISTOPAQUE-1077 (Sigma, St. Louis, Mo.) orFicoll-Paque Plus (Amersham Biosciences Piscataway, N.J.). Whole bloodis placed in Accuspin (Sigma) or LeucoSep (Greiner Bio-One, Inc.,Longwood, Fla.) centrifuge frit tubes containing density gradientmedium. The PBMC layer is collected and washed twice with DPBS or HBSSand re-suspended at 4×10⁶ cells/mL in RPMI complete (2-fold the finalcell density). The PBMC suspension is added to 96-well flat bottomsterile tissue culture plates.

Compound Preparation

The compounds are solubilized in dimethyl sulfoxide (DMSO). Thecompounds are generally tested at concentrations ranging from 30-0.014μM. Controls include cell samples with media only, cell samples withDMSO only (no compound), and cell samples with a reference compound2-[4-amino-2-ethoxymethyl-6,7,8,9-tetrahydro-α,α-dimethyl-1H-imidazo[4,5-c]quinolin-1-yl]ethanolhydrate (U.S. Pat. No. 5,352,784; Example 91) on each plate. Thesolution of test compound is added at 7.5 mM to the first well of adosing plate and serial 3 fold dilutions are made for the 7 subsequentconcentrations in DMSO. RPMI Complete media is then added to the testcompound dilutions in order to reach a final compound concentration of2-fold higher (60-0.028 μM) than the final tested concentration range.

Incubation

Compound solution is then added to the wells containing the PBMCsuspension bringing the test compound concentrations to the desiredrange (usually 30-0.014 μM) and the DMSO concentration to 0.4%. Thefinal concentration of PBMC suspension is 2×10⁶ cells/mL. The plates arecovered with sterile plastic lids, mixed gently and then incubated for18 to 24 hours at 37° C. in a 5% carbon dioxide atmosphere.

Separation

Following incubation the plates are centrifuged for 10 minutes at 1000rpm (approximately 200 g) at 4° C. 4-plex Human Panel MSD MULTI-SPOT96-well plates are pre-coated with the appropriate capture antibodies byMesoScale Discovery, Inc. (MSD, Gaithersburg, Md.). The cell-freeculture supernatants are removed and transferred to the MSD plates.Fresh samples are typically tested, although they may be maintained at−30 to −70° C. until analysis.

Interferon-α and Tumor Necrosis Factor-α Analysis

MSD MULTI-SPOT plates contain within each well capture antibodies forhuman TNF-α and human IFN-α that have been pre-coated on specific spots.Each well contains four spots: one human TNF-α capture antibody (MSD)spot, one human IFN-α capture antibody (PBL Biomedical Laboratories,Piscataway, N.J.) spot, and two inactive bovine serum albumin spots. Thehuman TNF-α capture and detection antibody pair is from MesoScaleDiscovery. The human IFN-α multi-subtype antibody (PBL BiomedicalLaboratories) captures all IFN-α subtypes except IFN-α F (IFNA21).Standards consist of recombinant human TNF-α (R&D Systems, Minneapolis,Minn.) and IFN-α (PBL Biomedical Laboratories). Samples and separatestandards are added at the time of analysis to each MSD plate. Two humanIFN-α detection antibodies (Cat. Nos. 21112 & 21100, PBL) are used in atwo to one ratio (weight:weight) to each other to determine the IFN-αconcentrations. The cytokine-specific detection antibodies are labeledwith the SULFO-TAG reagent (MSD). After adding the SULFO-TAG labeleddetection antibodies to the wells, each well's electrochemoluminescentlevels are read using MSD's Sector HTS READER. Results are expressed inpg/mL upon calculation with known cytokine standards.

Assay Data and Analysis

In total, the data output of the assay consists of concentration valuesof TNF-α or IFN-α (y-axis) as a function of compound concentration(x-axis).

A plate-wise scaling is performed within a given experiment aimed atreducing plate-to-plate variability associated within the sameexperiment. First, the greater of the median DMSO (DMSO control wells)or the experimental background (usually 20 pg/mL for IFN-α and 40 pg/mLfor TNF-α) is subtracted from each reading. Negative values that mayresult from background subtraction are set to zero. Each plate within agiven experiment has a reference compound that serves as a control. Thiscontrol is used to calculate a median expected area under the curveacross all plates in the assay. A plate-wise scaling factor iscalculated for each plate as a ratio of the area of the referencecompound on the particular plate to the median expected area for theentire experiment. The data from each plate are then multiplied by theplate-wise scaling factor for all plates. Only data from plates bearinga scaling factor of between 0.5 and 2.0 (for both cytokines IFN-α,TNF-α) are reported. Data from plates with scaling factors outside theabove mentioned interval are retested until they bear scaling factorsinside the above mentioned interval. The above method produces a scalingof the y-values without altering the shape of the curve. The referencecompound used is2-[4-amino-2-ethoxymethyl-6,7,8,9-tetrahydro-α,α-dimethyl-1H-imidazo[4,5-c]quinolin-1-yl]ethanolhydrate (U.S. Pat. No. 5,352,784; Example 91). The median expected areais the median area across all plates that are part of a givenexperiment.

A second scaling may also be performed to reduce inter-experimentvariability (across multiple experiments). All background-subtractedvalues are multiplied by a single adjustment ratio to decreaseexperiment-to-experiment variability. The adjustment ratio is the areaof the reference compound in the new experiment divided by the expectedarea of the reference compound based on an average of previousexperiments (unadjusted readings). This results in the scaling of thereading (y-axis) for the new data without changing the shape of thedose-response curve. The reference compound used is2-[4-amino-2-ethoxymethyl-6,7,8,9-tetrahydro-α,α-dimethyl-1H-imidazo[4,5-c]quinolin-1-yl]ethanolhydrate (U.S. Pat. No. 5,352,784; Example 91) and the expected area isthe sum of the median dose values from an average of previousexperiments.

The minimum effective concentration is calculated based on thebackground-subtracted, reference-adjusted results for a given experimentand compound. The minimum effective concentration (molar) is the lowestof the tested compound concentrations that induces a response over afixed cytokine concentration for the tested cytokine (usually 20 pg/mLfor IFN-α and 40 pg/mL for TNF-α). The maximal response is the maximalamount of cytokine (pg/ml) produced in the dose-response.

The complete disclosures of the patents, patent documents, andpublications cited herein are incorporated by reference in theirentirety as if each were individually incorporated. Variousmodifications and alterations to this invention will become apparent tothose skilled in the art without departing from the scope and spirit ofthis invention. It should be understood that this invention is notintended to be unduly limited by the illustrative embodiments andexamples set forth herein and that such examples and embodiments arepresented by way of example only with the scope of the inventionintended to be limited only by the claims set forth herein as follows.

What is claimed is:
 1. A compound of the Formula (IV):

wherein: m is an integer from 1 to 5; R′ is selected from the groupconsisting of: hydroxy, thiol, —S(O)₀₋₂-alkyl, —S(O)₂—NH—R₉, alkoxy,—O—C₁₋₃ alkylene-S(O)₂-alkyl, —N(R₉)₂, and —NH-Q-R₄; Z is selected fromthe group consisting of: a bond, C₁₋₅ alkylene,

A′ is selected from the group consisting of: —O—, —C(O)—, —N(R₈)—,—N(Q-R₄)—, —N(C₁₋₅ alkylene-NH-Q-R₄)—, —N(C₁₋₅ alkylene-W—NH—R₈)—, and—S(O)₀₋₂—; R₂ is selected from the group consisting of hydrogen, alkyl,alkoxyalkylenyl, haloalkyl, hydroxyalkylenyl, and —X-Y-alkyl wherein Xis C₁₋₂ alkylene, and Y is selected from the group consisting of—N(R₈)—SO₂—, —N(R₈)—C(R₆)—, and —N(R₈)—SO₂—N(R₈)— R_(A′) and R_(B′) areeach independently selected from the group consisting of: hydrogen,halogen, alkyl, alkenyl, alkoxy, alkylthio, and —N(R₉)₂; R₄ is selectedfrom the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl,arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl,heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, andheterocyclyl, wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl,aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl,heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups canbe unsubstituted or substituted by one or more substituentsindependently selected from the group consisting of alkyl, alkoxy,hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto,cyano, aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy,heteroarylalkyleneoxy, heterocyclyl, amino, acetylamino, alkylamino,dialkylamino, (dialkylamino)alkyleneoxy, and in the case of alkyl,alkenyl, alkynyl, and heterocyclyl, oxo; R₆ is selected from the groupconsisting of ═O and ═S; R₈ is selected from the group consisting ofhydrogen, alkyl, alkoxyalkylenyl, and arylalkylenyl; R₉ is selected fromthe group consisting of hydrogen and alkyl; R₁₁ is selected from thegroup consisting of hydrogen, alkyl, halogen, and trifluoromethyl; R₁₂is selected from the group consisting of hydrogen, alkyl, phenyl,2-pyridyl, 3-pyridyl, and 4-pyridyl; Q is selected from the groupconsisting of a bond, —C(R₆)—, —C(R₆)—C(R₆), —S(O)₂—, —C(R₆)—N(R₈)—W—,—S(O)₂—N(R₈)—, —C(R₆)—O—, and —C(R₆)—N(OR₉)—; and W is selected from thegroup consisting of a bond, —C(O)—, and —S(O)₂—; or a pharmaceuticallyacceptable salt thereof.
 2. The compound or salt of claim 1, whereinR_(A′) and R_(B′) are independently hydrogen or alkyl.
 3. The compoundor salt of claim 2, wherein R_(A′) and R_(B′) are both methyl.
 4. Thecompound or salt of claim 1, wherein Z is selected from the groupconsisting of a bond and C₁₋₃ alkylene.
 5. The compound or salt of claim1, wherein Z is —(CH₂)₀₋₁-A′-(CH₂)₀₋₁—.
 6. The compound or salt of claim5, wherein A′ is —O—.
 7. The compound or salt of claim 5, wherein A′ is—N(R₈)— or —N(Q-R₄)—.
 8. The compound or salt of claim 7, wherein Q is—S(O)₂— and R₄ is C₁₋₄ alkyl.
 9. The compound or salt of claim 1,wherein the compound is of the following formula:

wherein: Z is a bond or C₁₋₃ alkylene; and R₂ is selected from the groupconsisting of hydrogen, C₁₋₄ alkyl, HO—C₁₋₄ alkylenyl, and C₁₋₄alkyl-O—C₁₋₄ alkylenyl; or a pharmaceutically acceptable salt thereof.10. The compound or salt of claim 1, wherein the compound is of thefollowing Formula:

wherein R₂ is selected from the group consisting of hydrogen, C₁₋₄alkyl, HO—C₁₋₄ alkylenyl, and C₁₋₄ alkyl-O—C₁₋₄ alkylenyl; or apharmaceutically acceptable salt thereof.
 11. The compound or salt ofclaim 1, wherein R′ is hydroxy.
 12. The compound or salt of claim 1,wherein R₂ is selected from the group consisting of hydrogen, alkyl,alkoxyalkylenyl, haloalkyl, and hydroxyalkyl.
 13. The compound or saltof claim 12, wherein R₂ is hydrogen, C₁₋₄ alkyl, HO—C₁₋₄ alkylenyl, orC₁₋₄ alkyl-O—C₁₋₄ alkylenyl.
 14. The compound or salt of claim 1,wherein R′ is selected from the group consisting of —NH₂ and —NH-Q-R₄,wherein: Q is selected from the group consisting of —C(O)—, —C(O)—O—,—S(O)₂—, and —C(R₆)—N(R₈)—, wherein R₈ is selected from hydrogen andC₁₋₄ alkyl; and R₄ is alkyl, aryl, arylalkylene, heteroaryl, andheterocyclyl, wherein the aryl group can be unsubstituted or substitutedby acetylamino, alkyl, alkoxy, cyano, and halogen.
 15. The compound orsalt of claim 1, wherein: R₂ is selected from the group consisting ofhydrogen, alkyl, alkoxyalkylenyl, and hydroxyalkylenyl.
 16. Apharmaceutical composition comprising a therapeutically effective amountof a compound or salt of claim 1, in combination with a pharmaceuticallyacceptable carrier.
 17. A method of inducing biosynthesis of at leastone of interferon-α or tumor necrosis factor-α in an animal comprisingadministering an effective amount of a compound or salt of claim 1 tothe animal.